PHYSIOLOGICAL REVIEWS

Vol. 71, No. 2, April 1991

Printed in U.S.A.

Molecular and Cellular Adaptation of Muscle in Response

to Exercise: Perspectives of Various Models
FRANK W. BOOTH AND DONALD B. THOMASON
Department of Physiology and Cell Biology, University of Texas Medical School, Houston, Texas; and
Department of Physiology and Biophysics, University of Tennessee Medical School, Memphis, Tennessee

I. Physiological Significance ........................................................................... 541

A. Significance of adaptations to environment ..................................................... 541
B. Significance of adaptations to exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
C. Causes of fatigue in skeletal muscle during physical exercise .................................. 542
II. Classification of Models Closely Mimicking Human Physical Activity and Models of Increased
Contractile Activity That Do Not Mimic Human Exercise .................................... 544
A. Human physical activity ......................................................................... 544
B. Animal models that closely mimic human physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
C. Animal models of increased contractile activity that do not mimic human physical activity . 544
D. Increased contractile activity in tissue cultures of muscle cells ................................ 545
E. Terminology ...................................................................................... 545
III. Response of Cellular Processes in Skeletal Muscle to Single Bout of Exercise .................... 545
A. Glucose uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
B. Malonyl-coenzyme A ............................................................................. 547
C. Sarcoplasmic reticulum .......................................................................... 547
IV. Adaptation of Skeletal Muscle to Repeated Bouts of Aerobic Exercise ............................ 547
A. Mitochondria ..................................................................................... 547
B. Glycolytic enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
C. Lactate dehydrogenase .......................................................................... 555
D. Myosin isoform switching ....................................................................... 556
E. Oxygen flux ....................................................................................... 559
V. Adaptation of Skeletal Muscle to Repeated Bouts of Resistance Exercise ......................... 560
A. Human physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
B. Animal models mimicking human heavy-resistance training .................................. 560
C. Adaptations differ in aerobic and strength training ............................................ 561
VI. Hypertrophy in Animal Models Not Mimicking Human Physical Activity ........................ 561
A. Adaptations differ between certain animal models and humans ............................... 561
B. Animal models of stretch-induced hypertrophy ................................................ 562
C. Animal models of compensatory overload-induced hypertrophy ............................... 563
VII. Muscles or Muscle Cells in Culture Do Not Mimic Human Physical Activity ..................... 564
VIII. Regrowth of Atrophied Skeletal Muscle ............................................................ 565
IX. Summary of Inferred Sites for Gene Expression in Those Animal Models That Closely Mimic
Human Physical Activity ....................................................................... 566
X. Adaptations That Affect Cardiac Output ........................................................... 566
A. Stroke volume adaptations ...................................................................... 567
B. Chronotropic adaptations ........................................................................ 572
XI. Adaptations That Affect Cardiac and Peripheral Blood Flow ...................................... 573
A. Coronary blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
B. Muscle blood flow ................................................................................ 573
XII. Adaptations That Affect Cardiac Myocyte Metabolism ............................................ 574
A. Substrate metabolism ............................................................................ 574
B. Oxidative phosphorylation ....................................................................... 574
XIII. Conclusion ........................................................................................... 574

I. PHYSIOLOGICAL SIGNIFICANCE for adaptation to changes in the environment likely

A. SigniIcance of Adaptations to Environment carry over to some of the adaptations occurring because
of physical training. Prosser (316,317) has written that
The ability of an animal to adapt to repeated bouts cellular, organ, and systemic alterations that favor sur-
of physical exercise over a period of weeks such that viva1 of an animal to an environmental change are said
exercise capacity is improved is termed physical train- to be adaptive. Physical exercise, like environmental
ing. Some of the inherent mechanisms that are crucial change, disrupts the milieu interieur. Fisher (103) has

0031-9333/91 $1.50 Copyright 0 1991 the American Physiological Society 541

542 FRANK W. BOOTH
emphasized that biochemical and physiological adapta-
tions to a changed environment or physiological stimu-
lus fall into two categories based on their duration. Cel-
lular, organ, or systemic alterations that occur on the
same time scale as a single exercise bout are said to be
acute exercise responses. On the other hand, changes in
cells, organs, or systems that persist for appreciable pe-
riods after or as a consequence of physical training are
said to be exercise adaptations. A function of exercise
adaptation seems to be to minimize disruption of homeo-
stasis during an exercise bout. It is this better mainte-
nance of the milieu interieur by the exercise adaptations
that favors the functional effectiveness of the animal
beyond the resting state. Less disruption in homeostasis
permits the animal or human to undergo physical work
for longer durations at the same absolute power before
fatigue. This review considers molecular and cellular re-
sponses to exercise that may signal molecular and cellu-
lar adaptations during physical training.
B. Signijicance of Adaptations to Exercise
This review is organized to use some of the known
causes of fatigue during physical exercise as links be-
tween molecular and cellular changes that occur as a
result of physical training and the chronic adaptations
that are characteristic of physical training. One can
speculate that adaptations that improved an animal’s
work capacity enhanced its survival. The genetic ability
to alter exercise performance through physical training
has not been lost along the evolutionary scale. Conse-
quently, not all known molecular and cellular changes to
exercise are considered here; this is because their func-
tion may not yet be recognized to be associated with
adaptations that ameliorate fatigue. In addition, this
review does not repeat in great detail material that is
available in other reviews. There are 11,689 documents
for the Medline MESH word “exertion,” Medline’s term
for exercise, between 1984-1989, inclusive. To the reader
unfamiliar with the causes of fatigue during physical
-exertion, enough description has been given (Table 1) to
permit understanding of the physiological significance
of the molecular and cellular events. A more detailed
review on fatigue is available (108). In addition, the
reader is referred to earlier reviews that have compre-
hensively documented biochemical responses to a single
exercise bout and biochemical adaptations of muscle to
physical training.
C. Causes of Fatigue in Skeletal Muscle During
Physical Exercise
Fatigue is defined as the inability of the animal or
human to continue working at a given exercise intensity.
Thus a reduction in power output is seen as fatigue
(291). This section briefly delineates how various causes
of fatigue (Table 1) prevent an animal or a human from
being able to continue working at a given rate or level of
AND DONALD B. THOMASON Volume 71
activity. Fatigue mechanisms thus cause an individual
either to exercise at a lower intensity or to stop exercis-
ing altogether. The reader is referred to an excellent
review by Gollnick (132) for a more in-depth coverage of
energy metabolism during prolonged exercise.
I. Adenosine triphosphate depletion
The interaction of the myosin and actin filaments
during muscle contraction is powered by ATP. Through
a complex series of molecular events, energy from the
binding and enzymatic cleavage of ATP to ADP and Pi
powers the formation of the myosin-actin cross bridge,
conformational translocation of the opposing filaments,
and release of the cross bridge to begin the cycle again.
Thus each cycle of myosin and actin cross-bridge forma-
tion consumes an ATP molecule. Furthermore, the pul-
satile increase in sarcoplasmic free Ca2+ during contrac-
tion initiates cross-bridge cycling; additional ATP is
consumed in releasing and sequestering Ca2’. New-
sholme and Leech (291) speculate that the small de-
creases in ATP concentration in skeletal muscle during
an all-out sprint would diminish myosin adenosinetri-
phosphatase (ATPase) activity and hence cross-bridge
cycling, in turn preventing continued sprinting at the
same pace. Also a decreased ATP concentration would
decrease Ca2’ cycling and possibly contribute to fatigue.
2. LowpH
After continuous high-intensity exercise to exhaus-
tion, intramuscular pH can decrease to 6.6-6.3 (171,274,
336). In working muscle, the decrease in muscle power
(work per unit of time) at low pH is attributed to proton
interference with the catalytic activity of many en-
zymes (292). Increased free H+ could produce some, or
all, of the following metabolic processes. They are inhibi-
tion of phosphofructokinase activity (74, 135, ZZO),
which would diminish ATP production via glycolysis;
decrease of glycogen breakdown by inhibition of phos-
phorylase kinase and adenylate cyclase activity and by a
shift from HPOZ- to H,PO, (59); decrease in maximum
tension due to increased free Ca2’ required to obtain the
same submaximal tension (86); increase in the constant
for. the apparent binding of Ca2’ to troponin (117),
thereby attenuating the contractile response (223); and
decrease in Ca2+ release from the sarcoplasmic reticu-
lum (289), which would decrease muscle tension. For fur-
ther discussions on muscle fatigue, see References 108,
153,291,328,336, and 414.
Force production by muscle is also reduced by the
formation of the diprotonated form of Pi (H,P0,)(295).
Because Pi and H+ both increase in muscle undergoing
intense exercise, the shift in equilibrium causes force to
decrease.
3. Glycogen depletion
A relationship between carbohydrate depletion and
fatigue was demonstrated by Christensen and Hansen
April 1991 EXERCISE TRAINING ADAPTATIONS 543

TABLE 1. Fatigue types and characteristics, causes, adaptations to delay fatigue onset during exercise, biochemical
basis of adaptation, and molecular/cellular signals implicated in adaptation

Molecular and
Energy From, % Cellular Responses
Some Types Time to Cause of Adaptive Strategies Biochemical Basis Signaling
of Fatigue Fatigue Anaerobic Aerobic Fatigue to Delay Fatigue of Adaptation Adaptation

All-out running -10 s 100 0 ATP and CP Deplete less ATP ATP resynthesis ?
sprint of depletion per unit of power processes; more
100 m efficient use of ATP
All-out 1,500-m -4 min 35 65 High Pi Less reliance on Increased mitochondria CAMP? ATP flux?
run Low pH glycolysis ADP or ATP
Less increase levels?
in muscle and
blood lactate
concentrations
Marathon run -2h 0 100 Glycogen Carbohydrate Increased mitochondria CAMP? ATP
of 26 miles depletion sparing Decreased glycolytic level?
enzymes ADP or ATP?
Maximal O2 Increased maximal Improved Ca2’ influx ?
flux stroke volume Increased blood volume
and cardiac Other?
output
Increased O2 flux Increased capillary FGF?
through skeletal density CAMP?
muscle Increased myoglobin Other?
concentration
Increased mitochondria
Lifting heavy -1 min 100 0 Insufficient Increase mass of 3 ?
objects mass of contractile
skeletal protein in
muscle skeletal muscle

Fatigue does not derive from a single cause. Thus different human sports have unique sources of fatigue. This table is not inclusive to all
types of fatigue. Fatigue is defined as a reduction in power output. CP, creatine phosphate; FGF, fibroblast growth factor. [Adapted from
Newsholme (290) and Fitts and Metzger (108).]

in 1939 (61). In this experiment, subjects exercised until Two acute responses to conserve glycogen stores during
exhaustion, at which time the subjects were hypoglyce- aerobic exercise involve I) a shunting of blood glucose to
mic. Immediately, 200 g of glucose was given orally. working skeletal muscle for oxidation and 2) a mobiliza-
Within 15 min of glucose ingestion, the subjective symp- tion of fatty acid from fat depots, their transport to
toms of fatigue were gone, blood glucose had increased, muscle, and subsequent oxidation by muscle mitochon-
and these subjects were able to exercise for an addi- dria. In addition, an adaptive increase in mitochondrial
tional hour. It is possible that central and peripheral density as well as an adaptive decrease in the activity
nerves, which can only oxidize glucose, are a fatiguing levels of glycolytic rate-limiting enzymes induced by
tissue. aerobic training has been shown to play an important
Later it was shown that the human’s storage of car- role in sparing carbohydrate utilization as a fuel during
bohydrate is limited and is equivalent to +,OOO kcal aerobic exercise. Some of these exercise responses and
(56,291). In subjects performing aerobic exercise at 70- adaptations are discussed in sections III and IV.
100% of aerobic capacity, fatigue occurs at 1-2 h, and it
is associated with hypoglycemia (5), depletion of muscle
glycogen (4,31,170,355), and depletion of liver glycogen 4. Limited maximal oxygen flux
(5,18). The time to exhaustion at these work intensities
is altered by dietary manipulation of preexercise con- Aerobic training increases maximal oxygen flow
centrations of muscle glycogen; a carbohydrate-poor (VO 2max) (332). To this day, the underlying mecha-
diet results in the lowest concentrations of muscle gly- nism(s) accounting for the increase in Voamax (330) re-
cogen and the shortest time for work to fatigue, whereas mains controversial. Part of the reason for this contro-
a carbohydrate-rich diet is associated with the highest versy is related to the multiple adaptations that occur in
concentration of glycogen and longest work time (31). accordance with the increase in Vozmax. Maximal car-
Numerous strategies involving regulation of sub- diac output, capillary density in skeletal muscle, myoglo-
strate metabolism can be utilized by exercising organ- bin concentration in skeletal muscle, and mitochondrial
isms to conserve carbohydrate stores and thus lengthen density of skeletal muscle all increase in response to
the exercise duration before exhaustion. Theoretically, aerobic training. Each of these factors is thought to con-
such adaptive strategies could enhance survivability. tribute to the increase in Vozmax. Many researchers in
544 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

the exercise sciences believe that maximal cardiac out- C. Animal Models of Increased Contractile Activity
put limits VOzmax in healthy humans who are 550 yr old That Do Not Mimic Human Physical Activity
when exercise is performed at sea level (182, 332, 333,
340). Thus adaptive increases in the cardiovascular oxy- It is universally accepted that adaptations from a
gen-delivery system occurs in response to aerobic train- given type of increased contractile activity are specific.
ing. Because this adaptation improves physical perfor- Extrapolations of adaptations from one type of in-
mance, it is discussed in sections x and XI. The func- creased contractile activity to a different type are in-
tional significance of an increase in VOzmax in response valid in most cases. Therefore it is unlikely that animal
to aerobic training appears to be lengthening the dura- models of increased contractile activity that do not
tion that a given intensity of aerobic exercise can be mimic closely the recruitment pattern and duration of a
sustained until the organism becomes exhausted (182). human physical activity are valid models of that physi-
cal activity. This concept, although academically sound,
is not rigorously practiced when data are interpreted in
original research articles.
5. Insuficient mass of skeletal muscle Examples of different adaptational responses be-
tween animal models of increased contractile activity
The capacity of skeletal muscle to produce force per that do not mimic a human physical activity are dis-
unit cross-sectional area is not altered after heavy-re- cussed next. For example, the model of swimming of
sistance training (341). Thus an adaptive increase in rats in tanks does not mimic human swimming. Colle-
muscle cross-sectional area would distribute the same giate male swimmers who trained intensely for 6 mo
absolute load over a larger cross section, decreasing load had an 82% greater citrate synthase activity per gram
per unit of cross section. of deltoid muscle (106). Even when rats are “swum” for 6
h/day for 3 mo, only a 25% increase in citrate synthase
activity (per gram muscle) in skeletal muscle occurs.
Part of the reason is that rats spend considerable time
II. CLASSIFICATION OF MODELS CLOSELY MIMICKING
during the exercise bout below the surface of the water
HUMAN PHYSICAL ACTIVITY AND MODELS OF
doing little continuous repetitive muscular contraction.
INCREASED CONTRACTILE ACTIVITY THAT They just sit on the bottom of the tank for extended
DO NOT MIMIC HUMAN EXERCISE periods. In contrast, the pattern of contractile activity
in human skeletal muscle is a repetitive cycling of limbs
One of the least appreciated necessities in apprais- for a continuous duration of many minutes without a
ing the exercise literature is to relate each exercise period of inactivity at the bottom of the pool. Further-
model to its proper human sports activity. Because more, the cardiovascular response of rats to swimming
adaptive responses to physical training are specific to is opposite to the response seen in human swimming
the type of exercise, an exercise model must closely or (14). During swimming, the heart rate and mean arte-
exactly mimic the human sports activity to extrapolate rial pressure in rats decreases (375); in humans, heart
the findings from animals to a specific human sport. We rate can increase to near-maximal values during swim-
arbitrarily divide models of increased contractile activ- ming (265). Therefore the swimming rat model does not
ity into four categories. mimic human swimming.
A second animal model of increased contractile ac-
tivity that does not mimic a human physical activity is
continuous chronic electrical stimulation. First, the re-
A. Human Physical Activity cruitment pattern of muscle fibers differs. Continuous
electrical stimulation usually recruits all fibers for ex-
Examples of human physical activities are jogging, tended durations of 812, or 24 h/day. Indeed, because of
swimming, cycling, resistance exercise, or weight its continuous pattern, Swynghedauw (380) called it
lifting. “permanent activation of skeletal muscle.” In contrast,
human running has an ordered recruitment of muscle
fibers [at low intensities of running, type I fibers are
preferentially recruited; at higher running intensities
B. Animal Models That Closely Mimic Human Physical or after prolonged submaximal running, type II fibers
Activity are also recruited (for review see Ref. 341)]. Second,
there is a difference in some of the acute responses that
The examples of animal models that mimic human occur with continuous electrical stimulation and run-
physical activities are few. Some are the running of rats ning. Skeletal muscles that undergo chronic continuous
on motor-driven treadmills or animal models where stimulation exhibit a 300% increase in chloride space
heavy-resistance work is accomplished within the pe- throughout the Znd-10th wk of stimulation (167), a pro-
riod of 1 h with no exercise for the remainder of the day. gressive increase in intracellular Ca2+ concentration un-
Rats running on treadmills have a unique order of fiber til it is 300% higher at the 2nd wk of stimulation, then a
recruitment (197). progressive decrease (Ca2’ was determined after dis-
April 1991 EXERCISE TRAINING ADAPTATIONS 545

continuing stimulation and anesthetizing the rabbits) activity in cultured muscle cells, but neither of these
(369), and finally a 25% decrease in muscle size after 3 mimics exactly a human physical activity because of the
wk of stimulation (425). It is unlikely that chloride space absence of the load of the body or the absence of sys-
and Ca2’ concentration are altered at the 2nd wk of temic responses, such as neural, hormonal, and immuno-
treadmill running for 2 h/day. Muscle size is unaltered logical.
by 2 h/day of running by rats (181). Another difference
between chronic stimulation and intermittent running
is that ,&adrenergic receptor density increases 320% on E. Terminology
the hearts of rats with chronically stimulated skeletal
muscle (239) but that ,&adrenergic receptor density is The word exercise is defined as “active: bodily exer-
unchanged on hearts from rats who have undergone tion for the sake of restoring the organs and functions to
daily bouts of running on motor-driven treadmills (426). a healthy state or keeping them healthy” (Stedman’s
Thus the model of continuous stimulation of skeletal Medical Dictionary, 24th ed.) and as “regular or re-
muscle does not mimic the human sport of running. peated use of a faculty or bodily organ or bodily exertion
There is no single regimen for human strength for the sake of developing and maintaining physical fit-
training. However, it is generally agreed that the major ness” (Webster’s New Collegiate Dictionary, 8th ed.).
lift exercises (press, pulls, and squats) are seldom prac- These definitions of exercise can be applied to human
ticed for >2 days/wk (44). If these lifts are practiced too physical activities and to most animal models that
frequently and too intensely, overtraining invariably closely mimic human physical activity, because these
results (44). Within a training day, for the purposes of activities involve repeated body exertion invoking multi-
building muscle mass, a large number of sets (5-7) and a ple organ systems-for periods of <2 h/day. On the other
moderate number of repetitions (4-7), using moderate hand, it is less than precise to employ the term exercise
amounts of weight (-80% of 1 repetition maximum), to animal models of increased contractile activity that
are employed (44). Approximately O.l-0.2% of the time do not mimic a human physical activity or to increased
within a week is spent training the muscle. Such train- contractile activity in tissue cultures of muscle cells.
ing produces an enlargement rate of 0.23% /day for the These models often do not include the entire body or
cross-sectional area of elbow flexors during isometric evoke the appropriate responses of multiple organ sys-
training by humans (201). tems or do not have alternative cycles of short exercise
Certain animal models for muscle hypertrophy do bouts with long rest intervals between the repeated
not mimic the work schedule of human training pro- bouts.
grams. Although human programs of strength training
consist of a low repetition number against a high resis-
tance, some animal models induce hypertrophy of skele- III. RESPONSE OF CELLULAR PROCESSES IN SKELETAL
tal muscle by a regimen of continuous repetition (24 h/ MUSCLE TO SINGLE BOUT OF EXERCISE
day) at low resistance. Two such animal models (com-
pensatory overload and continuous stretch) produce a Three important processes are associated with a
much more rapid enlargement than is produced by hu- single exercise bout that could contribute to fatigue.
man strength training. When muscle’s synergists are They are glucose uptake, malonyl-CoA concentration,
disabled by surgical ablation, the remaining muscle en- and sarcoplasmic reticulum function.
larges at a rate of 0.86-3.95% /day over a period of weeks
in seven different reports (for references see Ref. 259).
During the first 5 days postsurgery, muscle enlarges A. Glucose Uptake
6.6%/day (294). A second animal model produces an
even faster rate of muscle enlargement. Muscle enlarges
at a rate of 11% /day during the first 5 days when the I. Description of response
muscle is continuously stretched by a weight (249). Both
of these models undergo a “permanent activation of skel- The acute response to a single bout of aerobic exer-
etal muscle” (for references see Ref. 380). In contrast cise is a shift of glucose uptake to exercising muscle
only 0.1% -0.2%) instead of 100%) of the available time is fibers away from most of the other organs (except the
devoted to increased contractile activity in human brain). This effect is coordinated by a decrease in
strength training. Thus the animal models of compensa- plasma insulin (162) that is caused by sympathetic inhi-
tory overload and continuous stretch do not mimic the bition of insulin release from pancreatic ,&cells (326).
human sport of resistance or strength training. Thus insulin-stimulated uptake of glucose is diminished
in most organs and tissues due to decreases in circulat-
ing insulin levels. Superimposed on the reduction in
D. Increased Contractile Activity in Tissue Cultures plasma insulin is a preferential shift of blood flow to
of Muscle Cells contracting skeletal muscle away from most other or-
gans, including noncontracting skeletal muscle (332), so
Either intermittent stretching (411) or electrical that the amount of glucose (concentration X flow rate)
stimulation (41) has been used to increase contractile presented per unit time to these other organs is dimin-
546 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

ished. However, the major factor increasing glucose up-
take into contracting skeletal muscle fibers involves an
increase in their insulin sensitivity (30, 71, 96, 204, 206,
280, 327). Noncontracting skeletal muscle, lung, and
liver respond to acute exercise with no change in insulin
sensitivity (206). King et al. (230) have proposed that the
key factor accounting for the increased whole body in-
sulin sensitivity observed in trained human subjects is
due to the persistent effects of the last bout(s) of exer-
cise as opposed to more long-term adaptations to train-
ing. The greatly increased insulin sensitivity of skeletal
muscle in the postexercise period likely functions to
permit the rapid muscle glycogen resynthesis that oc-
curs in the presence of low plasma insulin levels (145).
2. Glucose transporter response
The mechanism by which a single bout of exercise
increases the amount of glucose that is transported into
the contracting muscle appears to be due, in part, to a
recruitment of glucose transporters to the sarcolemma
from the cytosol and/or an increased turnover of glu-
cose transporters within the sarcolemma. In 1965, it was
reported that an acute bout of contractile activity in-
creased the rate of glucose uptake into skeletal muscle
by increasing the maximal velocity ( Vmax) of transport
without significantly altering the Michaelis constant
(K,) (183). From these results, the investigators pre-
dicted an increase in either the number or the turnover
of the glucose transporters within contracting skeletal
muscle. This prediction has recently been proven by nu-
merous laboratories. Each of these reports is considered
next. The compound cytochalasin B binds specifically to
glucose transporters and when radiolabeled provides an
index of the number of glucose transporters. With the
use of this technology, a twofold increase in D-ghmse-
inhibitable cytochalasin B-binding sites in purified
plasma membranes from the red gastrocnemius muscle
of rats was measured 1 h after a l-h treadmill run (177).
However, these investigators showed that the four- to
fivefold increase in glucose uptake into skeletal muscle
postexercise was proportionately larger than the two-
fold increase in glucose transporters incorporated into
the plasma membrane. Hirshman et al. (177) speculated
that an increase in the intrinsic activity of glucose trans-
porters may occur. The results from a second laboratory
(88) showed a threefold increase in glucose uptake, a
twofold increase in glucose-inhibitable cytochalasin B-
binding sites in isolated plasma membranes, and no
change in cytochalasin B binding in isolated intracellu-
lar membrane fractions in hindlimb skeletal muscle of
rats after a 45-min run on the treadmill. Douen et al.
(88) interpreted their results as a lack of an exercise-in-
duced decrease in cytochalasin B binding in the intra-
cellular membranes, thereby implying the existence of a
second recruitable transporter pool that is not in the
isolated intracellular membranes within the muscle
fiber. In a third laboratory (373), no change in cytocha-
lasin B binding to isolated sarcolemma was noted when
muscle samples were taken 15 min after the end of a
45-min treadmill run by rats. However, the Vmax of glu-
cose uptake increased 3.2-fold. Sternlicht et al. (373)
concluded that the increase in Vmax for glucose uptake
was due solely to an increased transport rate of existing
glucose transporters in the sarcolemma. In a fourth
study (119), the same isolation procedures used in both
the second (88) and third (373) studies were employed.
Both techniques gave similar results for this group in
that a 66% decrease was observed in the ratio of cyto-
chalasin B-binding sites in the intracellular membrane
relative to the plasma membrane of rodent gastrocne-
mius and quadriceps muscles immediately after a 2-h
treadmill run. Fushiki et al. (119) interpreted their re-
sults as an exercise-induced translocation of glucose
transporters to the plasma membrane during the exer-
cise. In a fifth report (141), the plasma membrane glu-
cose transporter number in rodent red gastrocnemius
muscle was shown to be elevated 63,77, and 0% immedi-
ately, 30 min, and 2 h, respectively, after a l-h run on the
treadmill. In the same samples, facilitated D-glucose
transport in plasma membrane vesicles was increased
310, 79, and 0% immediately, 30 min, and 2 h, respec-
tively, after a single exercise bout. Goodyear et al. (141)
concluded that the reversal of the exercise-induced in-
crease in transporter intrinsic activity is more rapid
than the reversal of the increased transporter number
because of the larger decrease in activity in the first 30
min after exercise. In a sixth study, an acute l-h run by
rats on a motor-driven treadmill approximately doubled
the number of glucose transporters and carrier turnover
number in skeletal muscle plasma membrane vesicles
(231). The mean affinity constant of the glucose trans-
porter was not altered. Evidence has been presented
that the increased insulin sensitivity in skeletal muscle
after swimming exercise results from an altered postre-
ceptor step after insulin binding (58). In summary, re-
cent studies conclusively show that the increase in glu-
cose uptake produced by an acute bout of exercise is due
to an increased recruitment of glucose transporters
from an internal storage pool to the sarcolemma and
also due to an increased turnover of glucose transport-
ers within the sarcolemma.
3. Control of glucose transporter response
Protein kinase C translocation during muscle con-
traction has been suggested to play a regulatory role
during contraction, possibly in the activation of glucose
transport. Only 2 min of repetitive tetanic contraction
caused a maximal translocation of protein kinase C
from the cytosol to the particulate fraction (325). The
experimental model was 60 200-ms trains of indirect
electrical stimulation of rat calf muscle. In a later study
it was shown that only 2 min is required for diacylgly-
cerol to increase twofold to its maximal value in calf
muscles during indirect stimulation at a similar contrac-
tion frequency as that reported in the above study (64).
However, the translocation of protein kinase C from the
April 1991 EXERCISE TRAINING ADAPTATIONS 547

cytosol to the particulate fraction did not peak until the also spares carbohydrate as a fuel for aerobic exercise is
10th min of contraction. The uptake of Z-deoxyglucose presented in section IV.
increased with an even slower time course. Cleland et al.
(64) concluded that the production of diacylglycerol may C. Sarcoplasmic Reticulum
be causal for the translocation of protein kinase C,
which, together with an accumulated exposure to Ca2’ Numerous reports show a decrease in the function
during contractile activity, might activate glucose trans- of the sarcoplasmic reticulum in fast-twitch muscles I)
port. after prolonged exhaustive exercise @8,54,55,107,352),
Other factors may play a role in the exercise-in- 2) after high-intensity exercise (55), and 3) during
duced stimulation of glucose uptake in contracting skele- chronic electrical stimulation (165,251). A 50% decrease
tal muscle. However, the findings on these factors are in both the initial rate and the total capacity of Ca2+
sometimes contradictory. Some papers report an in- uptake by isolated sarcoplasmic reticulum occurs on the
crease in insulin receptor number in the plasma mem- 2nd day of l&h/day indirect stimulation of fast-twitch
branes of skeletal muscle from chronic aerobically muscle. The decrease appears to be due to an inactiva-
trained rats (36,85,343), whereas other findings suggest tion of sarcoplasmic reticulum Ca2+-ATPase activity
no change in insulin receptor number (144,405). Never- without a change in its protein concentration or in its
theless, a humoral factor is required because in vitro isoform distribution (251). The 50% decrease in sarco-
contraction does not enhance the sensitivity of glucose plasmic reticulum Ca2+ -ATPase activity is apparently
transport to insulin (58). This factor is not insulin, be- causally related, according to Leberer et al. (251), to the
cause contractile activity of skeletal muscle in the hind- 50% reduction in ATP binding, as determined by the
quarter perfused without insulin increases muscle binding of fluorescein isothiocyanate (a competitor for
plasma membrane glucose transport by increasing glu- the ATP-binding site on the sarcoplasmic reticulum
cose transporter number and intrinsic activity (142). A Ca2+-ATPase).
correlation of 0.95 existed between the GLUT-4 isoform The functional significance of the decrease of sar-
of the glucose transporter and Z-deoxyglucose uptake in coplasmic reticulum Ca2+ -ATPase with different types
contracting skeletal muscle (166). Fast-twitch oxidative of muscle contractile activity is debatable. Some believe
muscle (type IIa) had the highest levels, whereas fast- that it could be the cause of muscle fatigue (28, 54, 55)
twitch glycolytic (type IIb) muscle had the lowest during acute contractile activity. On the other hand, Le-
GLUT-4 and Z-deoxyglucose uptake. There is no effect of berer et al. (251) suggested that decreased Ca2’ uptake
a single bout of exercise on both basal and insulin- by the sarcoplasmic reticulum in chronically stimulated
stimulated receptor autophosphorylation and on basal fast-twitch muscle could be a factor in the 300% in-
and insulin-stimulated exogenous kinase activity in any crease in free Ca2+, which was reported by Sreter et al.
type of skeletal muscle (405). On the other hand, insulin (369) in continuously stimulated fast-twitch muscle (a
receptor kinase activity increases in aerobically trained time delay existed between ending stimulation, anesth-
skeletal muscle (85,343). Acute exercise apparently does etizing rabbits, and taking muscle samples). Sreter et al.
not stimulate glucose transport via the ,&adrenergic re- (369) suggested that free Ca2’ is closely connected with
ceptor (372). Diacylglycerol and protein kinase C are the changes in gene expression associated with the fast-to-
most promising findings to date as a part of the signal slow fiber transformation (see sect. IvD). Another func-
cascade that is involved in the increased recruitment of tional consequence of the decreased uptake of Ca2+ by
glucose transporters into the sarcolemma during acute the sarcoplasmic reticulum is the parallel lengthening
exercise. of the time to peak tension and the half-relaxation time
(165). Whether the ATP cost of muscle work is altered at
the time of this change (the 4th day of continuous indi-
rect stimulation of fast-twitch muscle) is unknown.
B. Malon yl-Coenx yme A
IV. ADAPTATION OF SKELETAL MUSCLE TO REPEATED

Malonyl-CoA serves as a regulatory molecule to in- BOUTS OF AEROBIC EXERCISE

hibit fatty acid oxidation. Thirty minutes of treadmill Adaptation is defined here as a semipermanent
exercise by rats causes a 36% decrease in malonyl-CoA
change(s) occurring in the structural and/or functional
in the gastrocnemius muscle (427). This decrease in
properties of cells, tissues, and organ systems after
malonyl-CoA would decrease its inhibition of carnitine weeks of repeated exercise bouts. If daily exercise is dis-
acyltransferase I activity, thereby enhancing fatty acid
continued altogether, the adaptation is maintained for
oxidation. Winder et al. (427) speculated that the signifi-
several days before it begins to disappear.
cance of a reduction in malonyl-CoA in exercising mus-
cle is a contributing factor to the increase in fatty acid A. Mitochondria
oxidation in muscle that occurs during prolonged sub-
maximal exercise. Thus an acute response during pro- I. Description of adaptation
longed aerobic exercise is the shift to oxidation of fatty
acids, which in turn conserves the limited stores of car- In 1967, Holloszy (179) reported a twofold increase
bohydrate in the body. A similar adaptive response that in the capacitv of skeletal muscle to oxidize pvruvate in
548 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

rats that underwent 12 wk of aerobic training by run- radation rate. The mitochondrial markers examined
ning on a treadmill for 2 h/day. Concomitantly, the ac- were cytochrome c, citrate synthase activity, and 3-ke-
tivities of the enzymes of the mitochondrial electron toacid CoA-transferase activity. In this study, rats un-
transport chain doubled per unit of weight in the same derwent 2 h of treadmill running every day during
skeletal muscles of the trained rats. In addition, the training.
doubling of protein concentration for cytochrome c, a
protein in the electron transport chain, provided evi-
dence that the training adaptation in oxidative capacity +$..Messenger ribonucleic acid
involved an increased amount of protein and was not
due to an increased catalytic activity of the same An increase in the synthesis rates of proteins local-
amount of enzyme protein. Numerous investigators ized in the mitochondria of trained skeletal muscle
have verified the adaptive increase in mitochondrial could occur because of an increase in pretranslation
density in aerobically trained skeletal muscle in both (mRNA quantity), translation (increased utilization of
rats and in other species, including humans (for refer- mRNA), or posttranslation (increased assembly) or a
ences see Ref. 341). combination of these mechanisms. Clearly there is an
increase in mRNAs coding for mitochondrial proteins in
skeletal muscle undergoing increases in contractile ac-
Z. Localization of signal for adaptation tivity (Table 2).

The signal or inducer for the adaptive increase in

skeletal muscle mitochondrial density in response to 5. Control of protein expression
aerobic training appears to be an endogenous rather
than a systemic factor. For example, in human subjects, I) AEROBIC TRAINING. Only a single mRNA, cy-
if only a single leg undergoes aerobic training on cycle tochrome c mRNA, has been examined in skeletal mus-
ergometer (the contralateral leg is noncontracting), mi- cles of rats trained by treadmill running (Table 2). Simi-
tochondrial density increases only in the trained leg lar percentage increases in citrate synthase enzyme ac-
(281). In a study examining a wide spectrum of athletes, tivity and cytochrome c mRNA occur in skeletal muscles
succinate dehydrogenase activity (a protein on the inner at the 14th day of training (283). This suggests a pre-
membrane of the mitochondrion) was found to be high- translational control mechanism. Citrate synthase ac-
est in those skeletal muscle groups that were engaged tivity has been shown to be proportional to the volume
directly in the training (134). For example, bicyclists fraction of mitochondria within a muscle (45). Thus it
had twice the succinate dehydrogenase activity per can be deduced that a percentage increase in cy-
gram of skeletal muscle in their legs compared with tochrome c mRNA is likely proportional to the percent-
their arms; conversely, canoeists had 36% greater activ- age increase in mitochondrial volume fraction at the
ity in their arms than in their legs. Moreover, the in- 14th day of the treadmill-running program.
crease in mitochondrial density in aerobically trained In skeletal muscles of rats trained to run 2 h/day on
skeletal muscle appears to be independent of certain a motor-driven treadmill, enzymes for fatty acid oxida-
hormones. Increases in succinate dehydrogenase activ- tion and the respiratory chain increase 100%) while cer-
ity and mitochondrial protein per unit of skeletal mus- tain tricarboxylic acid cycle enzymes only increase 50%
cle weight have been shown to occur in aerobically (184, 277) and other tricarboxylic acid cycle enzymes,
trained hypophysectomized, thyroidectomized, or dia- such as citrate synthase, increase 100% (105). The rea-
betic rats (136). Thus the exercise response that signals son why one tricarboxylic acid cycle enzyme increased
the adaptive increase in mitochondrial density likely re- by a smaller percentage than fatty acid oxidation and
sides within the contracting muscle. respiratory chain enzymes in treadmill running is un-
known. Another study (75) shows the maintenance of a
constant proportion of the individual components of the
3. Protein synthesis inner mitochondrial membrane constituents during
their adaptive increase in skeletal muscle because of
An increase in mitochondrial protein synthesis, a aerobic training. We conclude that the proportional in-
decrease in mitochondrial protein degradation, or both crease in mitochondrial components likely implies some
would be needed to permit the adaptive increase of mi- role for an assembly control, which is a subcategory of
tochondrial density in aerobically trained skeletal mus- posttranslational control.
cle. A major role for an increase in synthesis rate was In studies where rats were run daily on motor-
deduced from the following results. Similar half-lives driven treadmills for different durations, the resultant
for the time course of the increase (training) and the new steady-state level of mitochondria is directly pro-
decrease (detraining) of selected mitochondrial proteins portional to the time spent running, up to a specific time
between their control and trained steady-state quanti- duration. Beyond this duration, further increases did
ties were interpreted as no effect on the protein degrada- not occur. In rats trained 10,30,60, or 120 min/day, the
tion rate of these mitochondrial proteins by aerobic percentage increase in citrate synthase activity and cy-
training (39,385,386); half-life is dictated solely by deg- tochrome c concentration in the gastrocnemius muscle
April 1991 EXERCISE TRAINING ADAPTATIONS 549

TABLE 2. Changes in mitochondrial proteins and their mRNAs as a result of increases in contractile activity
Increase in, %

Stimulation Enzyme mRNA for

Duration Enzyme activity enzyme Muscle Stimulated Reference

Animal model mimicking human physical activity: aerobic training by chronic treadmill running

100 min/day, Citrate synthase 30-41 Soleus, plantaris, red 283

14 days Cytochrome c 27-57 quadriceps,
gastrocnemius

Animal model that does not mimic human physical activity: permanent activation
of small group of,muscles by chronic indirect electrical stimulation

12 h/day, 28 Citrate synthase 400 700 Extensor digitorum 351

days longus
24 h/day, 3- Citrate synthase 178 Tibialis anterior, 239
5 days Cytochrome oxidase 123 extensor digitorum
,&subunit of F,ATPase 185 longus
24 h/day, 10 Citrate synthase 213,182 Tibialis anterior, 239,425
days Cytochrome oxidase 215,154 extensor digitorum
,&subunit of F,ATPase 197,192 longus
VIC subunit of
cytochrome oxidase 112
Cytochrome b 252
24 h/day, 21 Citrate synthase 500,557,336 Tibialis anterior, 239,425
days Cytochrome oxidase 412, 642 extensor digitorum
Cytochrome b 500, 654 longus
,&subunit of F,ATPase 265,219
VIC subunit of
cytochrome oxidase 220

progressively increased with the time of running each exercise duration and intensity (82). Roles for pretrans-
day. The data are (for citrate synthase and cytochrome lation, translation, and/or posttranslation events are
c, respectively) 15 and 12% (10 min), 57 and 31% (30 also demonstrated by another study. Cytochrome c pro-
min), 87 and 38% (60 min), and 128 and 92% (120 min) tein synthesis rate and cytochrome c mRNA are 81 and
greater than control (105). These observations imply 60%, respectively, of control values in the red quadri-
that the control mechanism(s) is titrated by exercise ceps muscle after 7 days of fixation in a shortened posi-
duration. Further discussion of this concept is merited. tion and are 192 and 126%, respectively, of control val-
A later study examined the variable of exercise inten- ues on the 4th day of recovery from the joint fixation
sity (running speed) in the context of exercise duration (284). Although its mRNA increases during recovery,
on the quantity of the adaptive increase in mitochon- the increase in cytochrome c protein synthesis rate is
drial density in skeletal muscle. Dudley et al. (89) found much greater. Therefore these data imply an increase in
that it is possible to induce the same increase in cy- pretranslational, translational, and posttranslational
tochrome c concentration in skeletal muscle, as seen control of cytochrome c protein expression when the
with longer exercise times, by employing faster running contractile activity of an atrophied skeletal muscle in-
speeds combined with shorter run times, provided the creases. Furthermore, the integration of these various
exercise duration exceeded a minimum threshold value control mechanisms may represent a general adaptive
(82). An increase in exercise intensity likely recruits response for control of mitochondrial protein expres-
more motor units (416). Thus mitochondrial concentra- sion during aerobic training of muscle.
tion per gram of whole muscle would be increased more II) CHRONIC ELECTRICAL STIMULATION. AS with
because additional untrained muscle fibers are re- aerobic training, although mRNAs encoding mitochon-
cruited per unit of time at higher speeds of running. drial proteins are increased in skeletal muscles under-
A minimal duration of daily exercise that is depen- going an electrically stimulated increase in contractile
dent on exercise intensity is necessary to induce a detect- activity, this increase in mRNA is not likely to be the
able increase in mitochondrial density (105). Further sole mechanism inducing an adaptive increase in mito-
increases in mitochondrial density are directly related chondrial density in the model of chronic continuous
to duration, but there is a maximal duration beyond stimulation. In Table 2, cases exist where the percentage
which further daily bouts of treadmill running do not increase in mRNA is less than the percentage increase
induce a further increase in mitochondria. These find- in its protein product. For example, the VIC subunit of
ings imply that the percentage increase in mitochon- cytochrome oxidase mRNA is 220% of the control level,
drial density by contractile activity is titrated by both whereas cytochrome oxidase enzyme activity is 412 and
550 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

tochrome-c oxidase enzyme activity exceeds the percent-

age increase in its mRNA. This implies the involvement
of translational and/or postranslational control in ad-
dition to pretranslational control during this later time
interval of stimulation. The latter example emphasizes
that, for a given mitochondrial protein, different combi-
nations of pretranslation, translation, and posttransla-
tion occur during the time course of its increased ex-
pression in response to chronic electrical stimulation.
Despite the complexity of mechanisms contributing
to the increased expression of individual mitochondrial
proteins in electrically stimulated skeletal muscle, it is
clear that their final concentration per gram of muscle
is maintained in constant proportion. For example,
Reichman et al. (319) found that during chronic electri-
cal stimulation experiments, increases in enzyme activ-
ity levels of terminal substrate oxidation (tricarboxylic
acid cycle, fatty oxidation, respiratory chain) occur in
OL 1.

0
* . * 1

10
* *. * 1

10
. . . . 1.

30
* . . 1.

40
. . * 1,

50
parallel to maintain a constant proportion of these en-
Period of stimulation (days) zymes. On the other hand, Chi et al. (60) noted that the
timing of the changes for individual enzymes in chroni-
FIG. 1. Time course of adaptive increases in citrate synthase cally stimulated muscle indicates that more than one
mRNA (top) and citrate synthase enzyme activity (bottom) during 1% kind of signal is operative.
h/day stimulation of fast-twitch muscle. Note discordance between
rates of increase for enzyme activity and mRNA. [From Seedorf et al.
A higher percentage of muscle fibers recruited
(35U.l could be used to explain why the percentage increase in
mitochondrial density is greater in chronic electrical
stimulation studies than in treadmill run training ex-
periments. Durations of treadmill running for >2 h/day
642% of control values in muscles that have undergone do not further increase mitochondria density in the
continuous electrical stimulation for 21 days. This and working skeletal muscles beyond 200% of control values
similar observations by Williams et al. (425) led them to in rats (386). On the other hand, %400-500% increases
state that “this finding suggests that pretranslational in respiratory and tricarboxylic acid cycle enzymes per
regulation alone is insufficient to account fully for the unit of muscle weight occur in muscles that are stimu-
changes in expression of the protein products of the lated either 12 (319) or 24 h/day (425) for 21 days. One
F,-ATPase and cytochrome oxidase subunit VIC genes. possible explanation for why the maximal increase in
Enhanced translational efficiency, accelerated trans- mitochondrial density is 500% of control in the electri-
port of these proteins from their cytoplasmic sites of cal stimulation studies compared with only 200% of
synthesis across the mitochondrial membranes, or in- control in muscles from treadmill run rats may be that a
creased stability of the proteins may also be required to
support the accelerated mitochondrial biogenesis in-
duced by electrical stimulation” (425).
In addition, the relative roles that pretranslation,
translation, and posttranslation play in increasing mi-
tochondrial density in chronically stimulated skeletal
muscle vary during the time course of stimulation. Dur-
ing the first 6 days of indirect electrical stimulation,
citrate synthase activity increases without any increase
in citrate synthase mRNA (351; Fig. 1). Then, from day
7-10 of stimulation, citrate synthase mRNA increased
600-700%. These researchers interpreted these results
as an enhanced translation of existing mRNA during
the initial increase in citrate synthase activity. In an- Cytochrome c oxidase
other example, the percentage increase in cytochrome-c Subunit mRNA
oxidase enzyme activity and cytochrome-c oxidase (% of control)
mRNA is similar after days 3-7 of indirect electrical FIG. 2. Parallel increase in mRNAs for 2 subunits of cytochrome-
stimulation (10 h/day) (192; Fig. 2). This implies that c oxidase are shown in relation to increase in cytochrome-c oxidase
pretranslational control is solely responsible for the in- enzyme activity during IO-h/day stimulation of fast-twitch muscle.
mRNAs are encoded by different genes. Subunit III is mitochondrially
creased enzyme activity with the stimulation protocol. encoded, whereas subunit VIC is nuclear encoded. Also note diver-
On the other hand, between the time interval of 14-35 gence from identity line after 14 days of stimulation. [From Hood and
days of stimulation, the percentage increase in cy- Pette (191).]
April 1991 EXERCISE TRAINING ADAPTATIONS 551

greater percentage of muscle fibers per unit mass are
activated by electrical stimulation.
In contrast to the observed increase in enzyme activ-
ities of aerobic metabolism after indirect electrical stim-
ulation of the tibialis anterior muscle of rats, guinea
pigs, and rabbits, 10 h/day of electrical stimulation did
not alter the basal levels of aerobic enzymes in mice
(358). Mice had high basal levels of aerobic enzymes.
This means that transgenic mice may not be applicable
to training studies concerned with aerobic enzymes.
6. Heme expression
The rate-limiting enzyme regulating heme synthe-
sis is &aminolevulinic acid synthase. The activity of this
enzyme in the red portion of the vastus lateralis muscle
in rats is doubled 17 h after a 4,000-m run on a treadmill
(185). At the same time postexercise, no change in cy-
tochrome c protein concentration occurs. This observa-
tion implies that upregulation of heme synthesis is an
early regulatory event mediated by .muscle contraction.
7. Factors regulating molecular changes
In view of the above observations, three potential
regulators of the increase in mitochondrial density by
aerobic exercise and by chronic stimulation are dis-
cussed. These include adenosine 3’,5’-cyclic monophos-
phate (CAMP), hypoxia, and creatine phosphate.
I) ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE AND
AEROBIC TRAINING. Kraus et al. (239) recently hypothe-
sized that an elevated level of CAMP within skeletal
muscle during its chronic continuous stimulation is the
signal for the increase in mRNAs transcribing proteins
of mitochondria. This section considers the evidence as
to whether this hypothesis for the nonphysiological
model of human exercise supports a similar hypothesis
for aerobic training. Immediately after a single run on a
motor-driven treadmill lasting either 5, 10, or 30 min,
CAMP concentration doubles in the red and in the white
quadriceps muscles (128). If an increase in CAMP is the
sole factor inducing the increased mitochondrial density
in aerobically trained skeletal muscle, then mitochon-
dria should be increased after weeks of training at these
durations. However, rats that undergo 13 wk of running
for 10 min daily on a motor-driven treadmill have no
significant change in mitochondrial density, whereas
rats that run 30 min/day for 13 wk have a 31 and 57%
increase in cytochrome c concentration and citrate syn-
thase activity per gram of muscle, respectively, in the
gastrocnemius muscle (105). Duration of the doubling of
CAMP concentration in skeletal muscle after either a IO-
or a 30-min run is unknown. However, in the heart, a
single 60-min run on a motor-driven treadmill results in
CAMP being increased for a 24-h period after the run
(306). Thus the postexercise duration of CAMP increases
in skeletal muscle requires documentation.
The remaining results related to a potential role for
CAMP as the signal causing mitochondrial proliferation
in aerobically trained skeletal muscle are data related to
,&adrenergic receptors. Because ,&adrenergic receptor
stimulation by agonists increases CAMP concentrations,
whereas ,8-adrenergic receptor blockage by antagonists
decreases CAMP, the strategy of numerous studies in
animals and humans has been to use pharmacological
manipulation of ,&adrenergic receptor activation in vivo
to monitor resultant changes in mitochondrial density
of skeletal muscle. Two-hour daily infusions of the syn-
thetic catechol dobutamine into human subjects during
3 wk of bedrest increased citrate synthase activity in
their vastus lateralis muscle but caused no significant
change in succinate dehydrogenase and cytochrome oxi-
dase activities (376). Conversely, the normally observed
increase in citrate synthase, cytochrome oxidase, ,&hy-
droxyacyl-CoA dehydrogenase, malate dehydrogenase,
and alanine aminotransferase activities found in aero-
bically trained skeletal muscle of rats is almost com-
pletely blocked by a dosage of propranolol that de-
creases exercise heart rate by 25% but not by the &-se-
lective blocker atenolol (211). Ji et al. (211) concluded
that “&-adrenergic mechanisms play an essential role
in the training-induced enzymatic adaptation in skele-
tal muscle.” Although chronic P-blockade does not pre-
vent an adaptive increase in mitochondrial enzymes in
the vastus lateralis muscle of humans after 8 wk of bicy-
cle training, the increase is not as great as occurs in the
placebo group. In this study, succinate dehydrogenase,
cytochrome-c oxidase, and ,8-hydroxyacyl-CoA dehydro-
genase activities do not increase as much compared with
placebo, whereas citrate synthase activities are unaf-
fected by the ,&blockade during training (377). ,&Adren-
ergic receptor density is increased in skeletal muscle as
a result of aerobic training (423). A correlation of 0.63,
or a probability of 36%) was obtained between succinate
dehydrogenase activity and ,8-adrenergic receptor den-
sity in the gastrocnemius muscles of rats examined
from control, swim-trained, and run-trained groups
(423). Thus many reports involving training studies sug-
gest a connection between an increase in either ,&adren-
ergic receptor density or an increase in CAMP levels and
an increase in mitochondria of skeletal muscle. How-
ever, some reports do not support this association.
A number of studies report that the ,8-adrenergic
receptor does not play a role in the exercise-induced ad-
aptation of mitochondrial enzymes. After 6 wk of daily
injections of L-epinephrine in sedentary rats, hearts hy-
pertrophy 11%, but respiratory capacity, citrate syn-
thase and succinate dehydrogenase activities, and cy-
tochrome c concentrations of skeletal muscles do not
change (101). Chronic ,&adrenergic blockade does not
prevent the exercise-induced increase in enzymes of skel-
etal muscle in rats (216). Ji et al. (211) speculated that
the failure of this study to observe a role for ,8-adrener-
gic receptors in the exercise-induced increase in mito-
chondrial density was due to an insufficient ,&blockade.
The adaptive increase in citrate synthase, succinate de-
hydrogenase, cytochrome-c oxidase, and P-hydroxyacyl-
CoA dehydrogenase activities by swim training of rats
552 FRANK W.BOOTH AND DONALD B.THOMASON Volume 71

is not prevented by adrenodemedulation and/or sympa-
thectomy (169). The potential role of CAMP as a signal
for mitochondrial biogenesis in aerobically trained
muscle requires more experimentation.
II) ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE AND
CHRONIC STIMULATION. Kraus et al. (239) interpreted
their data demonstrating an increase in CAMP during
electrical stimulation as a correlation between the in-
crease in CAMP and/or ,&adrenergic receptor density
and the increase in mRNAs for mitochondrial proteins.
An examination of their data reveals that the percent-
ages of increase in CAMP and mRNA are not always in
proportion to each other. The F,-ATPase mRNA is sig-
nificantly increased 85% in skeletal muscle after 3-5
days of chronic stimulation, but CAMP is unchanged
after 3 days of stimulation and unreported after 5 days
(239). The F,-ATPase mRNA remains doubled from the
3rd to the 10th day of stimulation, but CAMP triples in
concentration in the same time period of stimulation.
Finally, F,-ATPase mRNA remains doubled from the
10th to 21st day of stimulation while CAMP concentra-
tion in stimulated muscle decreases from 308 to 154% of
control. Further testing of the hypothesis, as suggested
by the originators of the hypothesis, is merited.
III) ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE AND
TISSUE CULTURE. In primary Cultures of rat muscle cells,
agents that increase intracellular concentrations of
CAMP have been consistently shown to increase the lev-
els of two enzymes of oxidative metabolism, fumarase
and malate dehydrogenase (250). In another study, only
NADH cytochrome-c reductase activity and glucose oxi-
dation are consistently increased by drugs that elevate
CAMP in myotube cultures derived from satellite cells
(112). Other mitochondrial enzymes are not consistently
increased by drugs that increase CAMP in the same
study. Data from another report (349) suggest that the
cascade of increased free Ca2+, increased prostaglandin
synthesis, and increased CAMP lead to an increase in
creatine kinase activity in fusing myoblasts. Indometh-
acin inhibits both the increase in CAMP and creatine
kinase under the above conditions. As cautioned, find-
ings in tissue culture must be replicated in whole ani-
mals during exercise to validly conclude that a response
in culture occurs in the animal during physical exercise.
IV)HYPOXIAANDAEROBICTRAINING. Increasedac-
tivities of succinic oxidase, 3-hydroxyacyl-CoA dehydro-
genase, citrate synthase, and cytochrome-c oxidase in
skeletal muscle have been reported in humans with pe-
ripheral arterial insufficiency that causes intermittent
claudification (53, 187, 189). These investigators re-
marked that the similarity of their findings with
changes after aerobic training suggest a “common trig-
ger mechanism” (187). Holm et al. (189) later suggested
that “the restricted supply of oxygen to the muscle tis-
sue might induce increased activity of the mitochondrial
enzyme succinic oxidase” in the condition of intermit-
tent claudification (188). The same investigators ob-
served that successful revascularization reduces the in-
crease in succinic oxidase activities of skeletal muscle
back toward control values (189). Another experimental
model has been employed. In human subjects, both legs
were separately trained on a single-leg ergometer. Ci-
trate synthase activity and myoglobin concentration in-
crease more in skeletal muscle from the leg that trained
under hypobaric conditions (PO, = 572 Torr) than from
the contralateral leg that trained under normobaric
conditions (388). Terrados et al. (388) suggested that a
lowered PO,, rather than a difference in substrate flux
(which they infer to be the same because work intensi-
ties were the same), is the causal factor for greater in-
creases in citrate synthase and myoglobin under hypo-
baric conditions. However, Saltin and Gollnick (341)
cited extensive circumstantial evidence against the hy-
pothesis that tissue hypoxia is the initial stimulator for
the exercise-induced increase in mitochondrial density
in aerobically trained skeletal muscle. Further recent
support against a role for hypoxia as a signal inducing
mitochondrial biogenesis is the report that strenuous
exercise in the expedition to Mount Everest and Lhotse
resulted in a decrease in the enzyme activities of citric
acid cycle and respiratory chain and an increase in glyco-
lytic enzyme activities (196). The data from hypoxia
studies cited above do not provide a definitive conclu-
sion.
V)HIGH-ENERGYPHOSPHATELEVELSANDAEROBIC
TRAINING. There is recent evidence that depletion of tis-
sue ATP and creatine phosphate may serve as a stimu-
lus to induce an increase in mitochondrial density in
skeletal muscle (244,356). Rats that ingest a diet of 1%
,&guanidinopropionic acid for 6 wk have a 90% decrease
in creatine phosphate and a 50% decrease in ATP in
skeletal muscle (104). After 6-10 wk of this diet, an in-
crease in the activities of citrate synthase, Z-oxoglutar-
ate dehydrogenase, and 3-hydroxyacyl-CoA dehydroge-
nase occurs in some of the fast-twitch muscles but not in
slow-twitch muscle (356). Cytochrome c mRNA in-
creases 60 and 67% in the white quadriceps and soleus
muscles, respectively, when rats are fed a 1% ,B-guani-
dinopropionic acid diet for 22 days (244). This observa-
tion infers that decreased ATP and creatine phosphate
concentrations in skeletal muscle could play a contribut-
ing role in upregulating mitochondrial density during
aerobic training. However, the red quadriceps muscle
demonstrated no change in cytochrome c mRNA quan-
tity when fed 1% ,&guanidinopropionic acid for 22 days.
Thus any role of high-energy phosphate depletion in in-
ducting mitochondrial biogenesis involves more than a
pretranslational step.
VI) HIGH-ENERGY PHOSPHATE LEVELS AND
CHRONIC STIMULATION. In the same model, continuous
electrical stimulation of fast-twitch muscle (which in-
creases CAMP) produces a 50% decrease in creatine
phosphate after 8 days; however, no apparent change
occurs within the first 30 h (168). All of the increase in
citrate synthase mRNA occurs between the 6th and 10th
day of chronic electrical stimulation (12 h/day) of fast-
twitch muscle (351), which is the time period associated
with the decrease in creatine phosphate. In summary,
data exist to support a hypothesis that a decrease in the
April 1991 EXERCISE TRAINING ADAPTATIONS 553

high-energy status of fast-twitch skeletal muscle can increase in Pi, and thus of H,PO,, resulting in a lessened
induce mitochondrial biogenesis. decrease in force production at the same power after
VII)HIGH-ENERGY PHOSPHATES AND SPRINTING. aerobic training. In addition, the increase in mitochon-
Because sprinting (anaerobic exercise) decreases high- dria of aerobically trained skeletal muscle provides an-
energy phosphates without an increase in mitochon- other adaptive function for sparing carbohydrate as a
drial density, an additional factor other than high-en- fuel for muscle contraction. Enzymes involved in the
ergy phosphates must be involved in mitochondrial bio- activation (cytosolic), transfer to intramitochondrial
genesis. The additional factor is duration. Thirty site (cytosolic and mitochondrial), and ,&oxidation (mi-
minutes, but not 10 min, of endurance running was nec- tochondrial) of free fatty acids are increased in aerobi-
essary to invoke a significant increase in mitochondrial cally trained skeletal muscle (279). These enzyme adap-
density in skeletal muscle (105). All-out sprint exercise tations correspond to trained skeletal muscle having an
has a duration of <l min. Thus the duration of reduced increased capacity to oxidize free fatty acids (279). Hol-
high-energy phosphate is not long enough to signal mi- loszy and Coyle (182) concluded that “the glycogen-
tochondrial biogenesis in a single bout of sprint exer- sparing effect of increased fat oxidation probably plays
cise. A combination of duration would be required with a major role in endurance that occurs with training.”
the decrease in high-energy phosphates to produce on Sparing carbohydrate oxidation during prolonged aero-
increase in mitochondrial density, if high-energy phos- bic work delays fatigue.
phates are the inducing signal for increased mitochon-
dria.
B. Glycolytic Enzymes

8. How adaptation alters fatigue

Some functional adaptations that could result from
an increase in mitochondrial density were suggested by
Holloszy in 1973 (180). Holloszy reasoned that changes
in ADP and/or ATP concentrations from their homeo-
static levels would be only one-half as much in skeletal
muscle with twice the mitochondria; after aerobic train-
ing both trained and untrained muscles consume equal
quantities of oxygen and produce similar amounts of
ATP from their mitochondria while working at the
same absolute power. Moreover, Holloszy suggested
that to produce the same amount of ATP per unit of
muscle, muscle with twice the mitochondrial density
would need only one-half of the change in ADP and Pi
levels to produce one-half the ATP amount per unit of
mitochondrial weight. The hypothesis that ADP and
ATP concentrations would need to be disrupted less
from their homeostatic levels to obtain the same abso-
lute ATP production in muscle has been verified. The
ATP levels in human skeletal muscle decrease less when
exercising at the same absolute power after training
compared with before training in humans (342). Two
additional studies verified and extended these findings
(65, 92). Both found that the concentration of ATP de-
creases less and that the concentrations of Pi, ADP, and
ammonia increase less at the same oxygen uptake in rat
skeletal muscle with high mitochondrial content. The
important metabolic consequence of the smaller disrup-
tion in these compounds is the predicted lower substrate
fluxes through creatine kinase, adenylate kinase, AMP
deaminase, and glycolysis as a result of the adaptive
increase in mitochondria in aerobically trained skeletal
muscle (65,92). These adaptive alterations in metabolic
flux would diminish the increase in lactic acid forma-
tion and carbohydrate depletion, thus delaying the on-
set of fatigue due to glycogen depletion. Because H,PO,
decreases force production in skeletal muscle (295), an
adaptive increase in mitochondria results in less of an
I. Description of adaptation
I) AEROBIC TRAINING. A decreased glycolytic flux in
skeletal muscle occurs at the same exercise intensity
after aerobic training compared with before training
(170). This adaptation occurs during aerobic training
because of a decrease in the maximal activity of glyco-
lytic enzymes per unit of skeletal muscle weight and
because of a decrease in allosteric factors that activate
phosphofructokinase activity at a given absolute work-
load.
The decrease in glycolytic enzymes after aerobic
training appears to be limited to fast-twitch red mus-
cles. After 12 wk of treadmill running by rats for daily
durations of 2 h/day, several glycolytic enzymes de-
creased ~20% in fast red skeletal muscle and increased
18-35% in slow red skeletal muscle (21); however, there
was no change in glycolytic enzymes in fast white skele-
tal muscle. In this particular study, exercise intensity
may not have been great enough to recruit the fast white
skeletal muscle. Baldwin et al. (20) noted among various
rat skeletal muscles a high correlation between the ac-
tivities of phosphofructokinase and actomyosin ATP-
ase, indicative of the greater reliance of fast white mus-
cle on glycolysis.
II) CHRONIC STIMULATION. Greater percentage de-
creases in glycolytic enzyme activities have been ob-
served during continuous (24 h/day) electrical stimula-
tion experiments, probably because the daily duration
of contraction was longer than in the Z-h daily running
protocol. During continuous stimulation of a fast-twitch
muscle comprised of red and white regions, aldolase ac-
tivity is reduced to 66 and 92% of control after 10 days of
stimulation and is further reduced to 26 and 41% of
control after 21 days of stimulation in the red and white
regions, respectively (239,425). During the first 2 wk of
chronic stimulation of the fast-twitch red and white ti-
bialis anterior muscle. no change in the maximal activ-
554 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

ity of phosphofructokinase and in the concentration of smaller increase in AMP than muscle with a low density
fructose 1,6-diphosphate occurred, but both decrease of mitochondria during exercise at the same absolute
80% during the subsequent 4 wk of stimulation. By the work intensity (65,92). An increase in AMP concentra-
5th wk of stimulation, both are at levels found in the tion results in an increased flux through AMP deami-
control slow-twitch soleus muscle (167). nase, the first reaction of the purine nucleotide cycle.
This enzyme catalyzes the deamination of AMP to IMP
and NH, (255), primarily in fast-twitch red muscle (91).
2. SigniJicance ofadaptive decrease in glycolytic At the same absolute work rate, NH, increases less in
enzymes muscle with a high mitochondrial density, thus activat-
ing glycolytic flux to smaller degree than in untrained
A theoretical analysis of the metabolic significance skeletal muscle.
of changes in enzyme activities was presented by Goll- Also associated with the adaptive increase in mito-
nick and Saltin (137). The model predicts that for glyco- chondrial density in aerobically trained skeletal muscle
lytic flux to be maintained at the same rate in aerobi- are increases in enzymes of ,&oxidation and the capacity
cally trained muscles with decreased glycolytic en- to oxidize fatty acids (279). The potential metabolic sig-
zymes, substrate concentrations would have to be nificance of increased fatty acid oxidation on glycolytic
higher in the trained muscles. This has not been shown flux is given by the following experiment. When plasma
empirically. Similar concentrations of glucose 6-phos- free fatty acids are increased experimentally in un-
phate were measured before and after training in the trained rats during treadmill running, glycogen deple-
vastus lateralis muscle of ll- to 13-yr-old boys at rest, at tion decreases in fast and slow red skeletal muscle and
500 m/min, at 750 m/min, and at maximal exercise on a citrate concentrations increase (323). In a later experi-
bicycle (95). The following logical deductions can be ment performed in situ to avoid the 5-min delay that
made. Glucose 6-phosphate levels reflect fructose 6- occurs when the animal stops running and the muscle
phosphate levels (the substrate for phosphofructokin- sample is obtained, citrate and glycogen concentrations
ase, the rate-limiting enzyme in glycolysis). If true, then are higher in stimulated muscle perfused with fatty
the substrate-driven reaction velocity of phosphofruc- acids than in the hindlimb perfused without fatty acids
tokinase in aerobically trained skeletal muscle would be (322). These investigators concluded that the higher ci-
decreased in fast-twitch muscles after training at the trate level in the muscle perfused with fatty acids inhib-
same absolute power, since the maximal activity of ited phosphofructokinase (322). A similar conclusion
phosphofructokinase per gram of muscle decreased has been made from the results of a human study. A
without any change in glucose 6-phosphate levels. No fat-rich diet, which causes an inhibition of glycolysis in
information exists on the effects of training on fructose skeletal muscle both at rest and at the 5th min of bicy-
2,6-diphosphate concentrations in skeletal muscle, al- cling, is associated with a higher citrate concentration
though its concentration decreases in the liver during in the quadriceps muscle (208). Jansson and Kaijser
exercise (84,429). Other modulatory factors of phospho- (208) concluded that inhibition of glycolysis may be me-
fructokinase are considered next. diated by the inhibition of phosphofructokinase by an
increased muscle citrate concentration. Thus both posi-
tive and negative allosteric modulators of phosphofruc-
3. Mitochondrial adaptations produce allosteric tokinase are altered in such a quantitative manner so as
modijications to phosphofructokinase to activate phosphofructokinase less in aerobically
trained skeletal muscle undergoing the same absolute
A decreased glycolytic flux in aerobically trained work rate as an untrained muscle. The decreased glyco-
skeletal muscle working at the same power is also pro- lytic flux that occurs during submaximal aerobic exer-
duced by a decreased allosteric activation of phospho- cise serves to conserve the limited stores of carbohy-
fructokinase. As discussed in section IVAN, at a given drate in the body and thus extends the time of work
absolute work rate or power output the homeostatic until fatigue.
disruption of high-energy phosphates is less because of
the adaptive increase in mitochondrial density in aero-
bically trained skeletal muscle (65, 92). Because a de- 4. Messenger ribonucleic acid alterations
crease in ATP and corresponding increases in ADP and
Pi activate phosphofructokinase activity (292), smaller I) AEROBIC TRAINING. No data are known to exist.
changes in the concentration of these nucleotides at a II)CHRONICSTIMULATION. Apretranslationalmech-
given absolute work rate after training would produce anism appears to be the major, if not the exclusive, con-
less activation of phosphofructokinase so that glycolytic trol site for the decrease in glycolytic enzymes noted in
flux is less, the rate of carbohydrate depletion .is re- chronically stimulated skeletal muscle. Aldolase A
duced, and time for work until exhaustion is prolonged. mRNA is 27% of control after 10 days of indirect elec-
Furthermore, the adaptive increase in mitochondria trical stimulation of fast-twitch muscle (239), whereas
also diminishes the amount of increase in another acti- aldolase enzyme activity is 66 and 92% of control activ-
vator of phosphofructokinase activity, ammonia (NH,). ity after the same duration of stimulation in two differ-
Muscle with a high density of mitochondria shows a ent experiments (239,425). Thus a large decrease in al-
April 1991 EXERCISE TRAINING ADAPTATIONS 555

dolase A mRNA level precedes a decrease in its enzyme aerobic training, total lactate dehydrogenase activity
activity1 decreases in the gastrocnemius muscle of rats (138,277)
and humans (8, 222), decreases in fast-twitch fibers of
rats (21) and humans (9), increases in the slow soleus
5. Factors regulating molecular changes muscle of rats (21), decreases in slow-twitch fibers of
the vastus lateralis muscle of humans (9), and increases
1)CHRONIC STIMULATION. Provision ofpropranolol, in the rat heart (138,212). Total activity of lactate dehy-
a ,&adrenergic antagonist, to rabbits prevents a de- drogenase is either unchanged, (222, 390), increased
crease in aldolase A activity and its mRNA after 10 days (240), or decreased in muscle biopsies taken from
of electrical stimulation of skeletal muscle for 24 h/day. strength-trained muscle of humans (9). These reports
Propranolol inhibits some of the decrease in aldolase A thus indicate that although aerobic training decreases
mRNA (55% of control with propranolol vs. 29% of con- total lactate dehydrogenase activity in fast-twitch mus-
trol without propranolol) after 21 days of stimulation cle, strength training has no consistent effect on this
(239). Propranolol does not affect the increase in CAMP enzyme.
that occurs in the continuously stimulated muscles. In addition to a decrease in total activity, isoforms
Kraus et al. (239) concluded that the decrease in aldolase of lactate dehydrogenase in skeletal muscle shift be-
A mRNA in chronically stimulated skeletal muscle is cause of aerobic training (the isoform terminology used
not a consequence of direct regulation by CAMP. in the original reference is retained here). The relative
II) TISSUE CULTURE. Increasing CAMP in cultured activity of lactate dehydrogenase isoforms 1 and 2, ex-
muscle cells did not decrease the activity of glycolytic pressed as a percentage of total lactate dehydrogenase
enzymes (112, 250), as found in chronic stimulation of activity, is greater in aerobically trained subjects than
skeletal muscle. However, the addition of caffeine to in nonconditioned subjects (222). In a related study, the
cultured myotubes causes a decrease in the activities of Vmax and K, of lactate dehydrogenase increases and de-
phosphofructokinase, pyruvate kinase, and lactate dehy- creases, respectively, when lactate is used as the sub-
drogenase (112). These results were interpreted by strate in a homogenate of skeletal muscle of rats that
Freerksen et al. (112) to be a result of a prolonged in- had undergone 10 wk of treadmill running for 1 h/day
crease in cytosolic Ca” acting to trigger events that re- (212). Also the Vmax of this enzyme decreases when pyru-
sult in the downregulation of glycolytic enzymes in skel- vate is used as the substrate in these rat muscle homoge-
etal muscle. This idea, if held to be true, must include a nates (212). The shift in enzyme isoform is an adapta-
duration factor, because the adaptive response of phos- tion that decreases pyruvate transfer to lactate while
phofructokinase to high-resistance strength training is increasing lactate conversion to pyruvate in aerobically
variable. Maximal activity of phosphofructokinase in trained skeletal muscle of rats. In another report, a
strength-trained skeletal muscle has been reported to greater activity of lactate dehydrogenase isozyme 1 is
not change (155, 194), to increase (67, 240), and to de- observed in the slow-twitch fibers of endurance-trained
crease (390). Because cytosolic free Ca2’ levels increase humans than in untrained individuals (9). Chronic stim-
in strength-trained muscles, which show no consistent ulation of fast-twitch muscle also increases the heart
adaptive change in phosphofructokinase activity, an- isoform (isoform 1) of lactate dehydrogenase (359).
other explanation possibly is needed. It may be that the
minimal duration of the increase of free cytosolic Ca2’ 2. Messenger ribonucleic acid alterations
level in response to the strength-training stimulus is not
long enough to downregulate the pretranslational con- I) AEROBIC TRAINING. No data are known to exist.
trol of glycolytic enzymes. In addition to increasing cyto- II)CHRONICSTIMULATION. Apretranslationalmech-
solic free Ca2+, caffeine also increases CAMP and me- anism appears to be the exclusive control for the switch
chanical activity of the cell. Muscle cultures exposed to in lactate dehydrogenase isoforms that results from in-
caffeine not only have a downregulation of the certain creased contractile activity. In the study of Seedoff et al.
enzymes involved in glycolytic flux, but the activities of (351), a similar time course for the changes in activities
some proteins of the mitochondrial electron transport and mRNAs for lactate dehydrogenase isoforms were
chain (NADH cytochrome-c reductase and succinic cy- reported. A parallel increase in the protein subunit of
tochrome-c reductase) increase (112). However, in- the heart isoform of lactate dehydrogenase and its
creased CAMP without increased free Ca2’ does not de- mRNA occurs during chronic stimulation (12 h/day) of
crease glycolytic enzymes (112). rabbit extensor digitorum longus muscle. Likewise, pro-
portional decreases in the protein subunit and mRNA of
the muscle isoform of lactate dehydrogenase occurs
C’. Lactate Dehydrogenase during chronic stimulation (351). More of the H, isoform
of lactate dehydrogenase protein exists in slow than in
1. Description of adaptation and aerobic and strength fast muscle (191).
training 3. How adaptation alters fatigue
Daily running exercise affects total lactate dehydro- Concurrent with a decrease in glycolysis in aerobi-
genase activitv differentlv in various fiber tapes. After calls trained muscle is another adaptation that also
556 FRANK W. BOOTH AND
tends to lower lactate levels. The function of the train-
ing-induced decrease in the total activity of lactate dehy-
drogenase and in a shift to the heart isoform of this
enzyme in skeletal muscle is to lessen the increase in
lactate concentration muscle at a given level of absolute
power. Indeed this was demonstrated by Karlsson et al.
(221) in 1972. They observed smaller increases in lactate
concentration in the skeletal muscles of humans after
training when exercised at the same absolute power as
before training. The consequence of smaller increases in
muscle lactate during work would be an adaptive
lengthening of time before the onset of fatigue. The pK,
of lactic acid is 3.7. Increases in lactic acid would lower
pH in muscle. Further information on the functional
role of lactic acid during exercise can be found in
Brooks (43).
D. Myosin Isofbrm Switching
1. Human physical activity
Normal ambulatory activity by humans maintains
the expression of the slow myosin heavy-chain isoform
by fibers at some genetically set limit. Further physical
training results only in very small percentage shifts
from fast to slow myosin heavy chain.
Five studies have demonstrated histochemically a forms of myosin heavy chains and of troponins C, I, and
decrease in the percentage of type IIb fibers in skeletal
muscle of humans in response to long-term aerobic ex-
ercise training (7, 25, 195, 203, 357). However, the fiber
type replacing the histochemical type IIb is variable. A
significant increase in slow type I fiber percentage was
noted in two of the above reports (195,357) where train-
ing lasted 6 and 15 wk, a significant increase in fast type
IIa fibers with no change in type I fiber percentage was
reported in two studies (7,203) where training duration
was 8 and 24 wk, and no significant change in either type
I or IIa fiber percentage was found in an 8-wk training
study (25). An early study, which only examined the per-
centage of slow type I fibers, found no change from their
pretraining level after a 5-mo aerobic training program
(133). When type I fiber percentage has been shown to
increase by training, the increases were from 50 to 56%
(195) and from 41 to 47% (357). Thus small or no changes
in slow type I percentage occur in aerobically trained
human muscle when analyzed by histochemical proce-
dures on muscle biopsies.
Histochemistry classifies a fiber into broad catego-
ries of fast or slow. However, in the rat soleus muscle,
single muscle fibers have been shown to have both fast
and slow myosin heavy chains (120). Two populations of
fibers were observed. One type was identified histochem-
ically as slow and failed to react against fast myosin
antibodies (120). This population consisted entirely of
slow myosin heavy chains (321). However, the second
population of fibers in the rat soleus muscle was identi-
fied histochemically as fast but has both fast and slow
mvosin heavv chains (120. 321). Thus when fast fibers
DONALD B. THOMASON Volume 71
have small percentage shifts in myosin heavy-chain iso-
forms from fast to slow, they remain fast fibers by histo-
chemical analysis. We speculate that this explanation
could account for the variable observations in human
skeletal muscle as to whether aerobic training will shift
the myosin heavy chain from the fast to the slow iso-
form.
With the advent of the analysis of isoform type
within single muscle fibers, unequivocal evidence from
humans now exists for the shift from fast to slow in
aerobically trained skeletal muscle. In one of the human
studies, no significant increase in type I fiber percent-
age was detected with histochemistry; however, a shift
was noted within individual fast IIA fibers from exclu-
sive expression of fast myofibrillar protein isoforms to-
ward a mixed pattern of fast and slow isoforms, as de-
termined by one-dimensional electrophoresis of pro-
teins from fragments of the same fiber type (25). Other
reports support the idea that aerobic training increases
the percentage of “hybrid” fibers containing both fast
and slow isoforms. By histochemistry, 13% of the type II
fibers are converted into a fiber type demonstrating in-
termediate myofibrillar ATPase activity in the triceps
brachi muscle in men and women after a 36-day ski
event over 800 km (345). Isolated fibers demonstrating
the histochemical category of intermediate myofibrillar
ATPase activity were shown, using immunohistochemi-
cal analysis, to have a coexistence of slow and fast iso-
T (345). These findings are consistent with the reduced
VmLlx of individual type II fibers of the human deltoid
muscle after 6 mo of intense swimming training (106). A
decreased Vmax in single type II fibers would be caused
by an increased percentage of the slow myosin heavy-
chain isoform (321). Taken together, these findings from
humans suggest that small quantities of isoform
switching from fast to slow contractile proteins occur
after aerobic training.
A decrease from 57 to 48% of the fibers identified as
slow-twitch fibers, after application of a myofibrillar
stain, occurred after a sprint training program (207).
Training consisted of “all-out” sprints for either 15 or 30
s on a mechanically braked bicycle ergometer by hu-
mans. Training was performed 2-3 days/wk, with the
sprint number progressively increasing from 4 to 12
each day during the 4- to 6-wk program. Four other
sprint training experiments did not produce an increase
in the percentage of fast-twitch fibers in the trained
muscle (for references see Ref. 207).
2. Chronic stimulation
The type of switching of myosin isoforms that oc-
curs during chronic stimulation does not represent the
type of adaptation occurring in the sports training of
normal humans. Although there is a subtle change in
myosin isoforms when normal ambulatory humans un-
dertake a program of physical training, a massive shift
in myosin isoforms occurs when skeletal muscle is invol-
April 1991 EXERCISE TRAINING ADAPTATIONS 557

untarily recruited continuously for either 12 or 24 h/day slow isoforms during the 3rd to 7th wk of continuous
for several weeks. Chronic indirect electrical stimula- indirect electrical stimulation of rabbit fast-twitch
tion (24 h/day) of the rabbit tibialis anterior muscle muscle, implies a pretranslational control mechanism.
results in a synchronous switching from fast protein Heilig and Pette (164) also noted a switch from fast to
isoforms of myosin to slow protein isoforms. For the slow myosin light-chain mRNAs in rabbit fast-twitch
myosin light chains, switching of protein isoforms be- muscle after 28 days of indirect electrical stimulation
gins during the 2nd wk and is largely completed by the (12 h/day). They suggested that the induced transfor-
7th wk of chronic stimulation (46). In the same muscles, mation of myosin light-chain pattern was due to a
a downregulation of the fast type IIb myosin heavy switch in gene transcription. The initiation of the switch
chain starts at 2 wk, but the appearance of slow myosin in myosin light-chain isoform mRNAs precedes initia-
heavy-chain protein does not occur until the 4th wk of tion of the switch in myosin heavy-chain isoform mRNA
chronic stimulation (46,267). A similar experiment pub- in the rabbit skeletal muscle.
lished in the same year found that the switch of myosin A different time course of switching of myosin
light chains from fast to slow protein isoforms is more light-chain isoform occurs in fast-twitch muscle in rats
delayed. The switch in myosin light chains occurs dur- than that described for rabbits. Although a nearly com-
ing the 8th-13th wk of chronic indirect stimulation (24 plete switch from fast to slow myosin light-chain
h/day) in the rabbit tibialis anterior muscle (350). If mRNA occurs after -4 wk of indirect electrical stimula-
stimulation is only 12 h/day, smaller changes in protein tion in the rabbit (164,314), minimal switching occurs in
quantities of certain myosin light chains occur with no rats whose muscles were stimulated for a similar dura-
change in myosin light-chain 3f (350). In contrast to the tion (232, 233). An additional difference exists between
2-mo delay in switch of protein from fast to slow myosin the two animal species. Although control of switching
light chain, the activity of myosin light-chain kinase appears to be pretranslational in rabbits (164, 314), a
decreases by 50% after only 1 day when stimulating the more complex control is apparent in rats, as discussed
rabbit tibialis anterior muscle for 24 h/day (237). The next.
potential significance of decreased myosin light-chain The control mechanism altering the protein iso-
phosphorylation would be a shift of the pCa-tension re- forms of myosin light chains during chronic stimulation
lationship toward lower pCa values and an attenuation of rat fast-twitch muscle seems to be specific to the iso-
of isometric force (110). form. Although myosin light-chain isoform 2s protein is
In 1981, Kwong and Vrbova (243) reported that increased, no change in either its synthesis rate or
fast-twitch muscle from small vertebrates (rats) has mRNA is seen during chronic stimulation of fast-twitch
less switching to slow-type muscle during chronic IO Hz muscle (233). Kirschbaum et al. (233) suggested that
stimulation than does fast-twitch muscle from larger protein degradation of myosin light-chain 2s is reduced.
animals (rabbits and cats). They observed that despite An earlier study from the same laboratory (22) found no
the prolonged stimulation, the twitch duration of fast change in slow myosin light chains during chronic stim-
muscles in rats is changed little. They remarked that ulation (IO h/day for 56 days) of rat fast-twitch muscle.
this observation differs from the findings obtained ear- In addition, the percentage decrease in the protein
lier for rabbits and cats, which show that a slowing of quantity of myosin light-chain 3f is more than the per-
contraction speed is achieved by 10 Hz stimulation for a centage decrease in its mRNA. Kirschbaum et al. (233)
similar duration. Furthermore, they commented that it stated that “this might indicate an increased turnover
appeared that the synthesis of contractile proteins of of LC3f or the existence of additional posttranscrip-
the fast type is favored in small mammals. Likewise in tional regulations of LC3f expression.” On the other
the heart, Baldwin (14) indicates that the V, (fast) iso- hand, the percentage increases in the protein synthesis
zyme of cardiac myosin is greater in rodents than in rates, protein quantity, and mRNA quantity are similar
larger animals. for myosin light-chains If and Is, in chronically stimu-
Support for this concept has been made by the anal- lated fast muscles of the rat. Thus a pretranslational
ysis of myosin protein isoform composition. Although control is evident for these light-chain isoforms. In sum-
major increases in the protein isoforms of slow myosin mary, each myosin light-chain isoform exhibits differ-
light-chains 1s and 2s occur in rabbit fast-twitch muscle ent control sites (pretranslation, translation, and post-
during the 3rd-7th wk of continuous stimulation (24 h/ translation) during isoform switching produced by
day) (46), less extensive changes are reported in rats. chronic stimulation in rat fast-twitch muscle.
After 6 wk of chronic stimulation (IO h/day) of rat fast- Switching in myosin heavy-chain isoforms also
twitch muscle, changes in myosin are restricted to fast differs between rabbits and rats for chronically stimu-
isoforms. Myosin light-chain 3f and fast myosin heavy- lated fast-twitch muscle. Whereas slow myosin heavy-
chain IIb decrease while myosin light-chain If and fast chain protein is markedly increased between 21 and 28
myosin heavy-chain IIa increase (234). Only small days of continuous electrical stimulation of rabbit mus-
amounts of slow myosin heavy chain appear in rat skele- cle (46), no slow myosin heavy-chain protein is apparent
tal muscle stimulated 10 h/day for 28 days (233). in 56-day stimulated fast-twitch muscle of rats (232).
Pluskal and Sreter (314) concluded that the close In rats, myosin heavy-chain mRNA switching is re-
correlation between changes in mRNA and protein lev- stricted to fast isoforms during indirect electrical stimu-
els of mvosin light chains. as thev switch from fast to lation (10 h/dav) of fast-twitch muscle. A progressive
558 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

decrease of fast myosin heavy-chain IIb mRNA to
nearly undetectable levels occurs in the first 7 days of
stimulation of rat fast muscle (234). Fast myosin heavy-
chain IIa mRNA is markedly increased between the 4th
and 7th days of stimulation in the same rat muscle (234).
Thus a switch from the fast isoform of myosin heavy
chain found in low oxidative fast fibers (type IIb) to that
found in high oxidative fast fibers (type IIa) occurs
early and before any switches in the mRNAs for myosin
light chains in stimulated fast muscle of rats. Only
minor increases in slow myosin heavy-chain I mRNA
were observed from the 4th to 8th wk of stimulation
rat fast muscle (234).
The rapid decrease in fast myosin heavy-chain IIb
mRNA in chronically stimulated fast muscle in the rat
has been confirmed in rabbits. In the chronically stimu-
lated (24 h/day) tibialis anterior muscle of the rabbit,
fast myosin heavy-chain IIb mRNA per gram of muscle
is 43,36, and 8% of the contralateral control at the 4th,
lOth, and Zlst day, respectively (47). In the same rab-
bits, fast myosin heavy-chain IIb mRNA per gram of
extensor digitorum longus muscle is 50,19, and 33% of
contralateral control at the 4th, lOth, and Zlst day, re-
spectively, of continuous indirect electrical stimulation
(47). Thus, in both rats and rabbits, fast myosin heavy-
chain IIb mRNA rapidly decreases during continuous
excitation of fast muscle.
Correlations between the time courses of changes in
protein and their mRNA quantities have also been made
in rat skeletal muscle. An increase in fast myosin
heavy-chain IIa mRNA occurs between the 2nd and 4th
days of chronic stimulation of rat fast-twitch muscle
(234). However, in the words of Kirschbaum et al. (234),
“a remarkable delay” existed before fast myosin heavy-
chain IIa protein increased. These investigators sug-
gested that “regulatory steps might exist between tran-
scription and translation in heavy chain expression for
fast myosin heavy chain IIa.”
3. Decreased weight bearing
The removal of normal ambulatory activity results
in large shifts of the myosin isoforms in humans and
rats (397). The percentage of type I fibers in the vastus
lateralis muscle decreases from 54 to 43% after 6 wk of
limited mobility in a movable cast brace after knee sur-
gery to eight athletes (152). In a human case study, the
recovery of type I fibers after atrophy was documented.
The percentage of type I fibers in a cross-country skier
at the time of knee surgery was 81%) was 58% 6 wk after
limb immobilization from surgery, and was 86% after
intense training in the time period from 2-6 mo postsur-
gery (152).
Removal of the weight-bearing function of the slow
soleus muscle of the rat produces rapid and large
changes in the content and percent composition of slow
myosin (399). Approximately 84% of slow myosin pro-
tein is lost from the soleus muscle by the 28th day of its
nonweight bearing (399). After onlv 7-8 davs of non-
weight bearing by the slow soleus muscle of the rat,
total myofibrillar protein content and total slow heavy-
chain protein content are decreased by 26 and 30%, re-
spectively (399). Because myofibrillar protein synthesis
rate is decreased by 59% during most of the 7-day period
of nonweight bearing (396), it is likely that a reduction
in synthesis rate plays an important role in the down-
regulation of slow myosin protein expression. The lack
of any significant change in slow myosin heavy-chain
mRNA in the 7-day unwei .ghted soleus muscle suggests
that a decrease in translation of this mRNA plays the
of major role in decreasing synthesis of slow myosin
heavy-chain protein (396). In addition, a numerical mod-
eling analysis indicates that the degradation rate of
myofibrillar protein in the slow soleus muscle begins to
increase on the 3rd-4th day of its unweighting (396).
Thus a decrease in myofibrillar protein synthesis initi-
ates protein loss. After 1 wk of nonweight bearing, both
the decrease in myofibrillar protein synthesis and the
increase in myofibrillar protein degradation rate in the
soleus muscle maintain the continued loss of protein.
After 1 mo of nonweight bearing, the new smaller myo-
fibrillar protein mass in the soleus is maintained exclu-
sively by the decreased myofibrillar protein synthesis
rate. Therefore both translational and posttransla-
tional control mechanisms, although differing in time
and magnitude, play roles in the approach to a new
steady-state level of protein expression in the non-
weight-bearing soleus muscle. A pretranslational con-
trol mechanism also becomes active, although to a lesser
extent, as evidenced by the de nova synthesis of addi-
tional myosin isoforms (399) and the expression of their
mRNAs (396).
If a slow soleus muscle is permitted 28 days of recov-
ery from 56 days of nonweight bearing, slow myosin
protein increases from 2.1 to 11.2 mg/pair soleus mus-
cles (399). Normal controls have 13.4 mg slow myosin/
pair soleus muscles. Thus, in contrast to fast muscle of
the rat where slow myosin gene expression is resistant
to change by continuous electrical stimulation, slow
myosin gene expression in slow muscle changes greatly
in response to weight-bearing exercise. Furthermore, if
adjunct treadmill-running exercise is provided during
or after the nonweight bearing, fast isoforms of myosin
are upregulated in addition to the recovery of slow myo-
sin content (398). These data, taken collectively, indicate
the complexity of the control mechanisms by which nor-
mal contractile function can influence the quantity and
quality of protein expression.
4. Factors regulating myosin isoform switching
A switch from fast to slow myosin isoforms has
been shown to occur after chronic administration of ei-
ther a &-adrenergic antagonist or a chemical that de-
creases muscle ATP and creatine phosphate. Treatment
of rats for 8 wk with the &-antagonist butoxamine
causes a 13% decrease in the cross-sectional area for
tvee II fibers without affecting tvpe I fiber size in the
April 1991 EXERCISE TRAINING ADAPTATIONS 559

soleus muscle (440). In addition, the percentage of type I
fibers increases from 68 to 83% of total fibers in the
soleus muscle and from 2 to 6% in the extensor digi-
torum longus muscle. Interestingly, chronic administra-
tion of the &-adrenergic agonist clenbuterol has the op-
posite effect. Type I fiber percentage decreases from 88
to 63% of the total fibers in the rat soleus muscle (440).
These data imply that increased CAMP would decrease
the percentage of type I fibers. If true, this observation
would conflict with the finding of increased CAMP and
increased type I fibers in chronically stimulated fast-
twitch muscle (239). Thus a change in a single regula-
tory signal is insufficient to explain a change in contrac-
tile protein isoform by contractile activity.
A chronic decrease in ATP and creatine phosphate
in rats fed a 1% ,&guanidinopropionic acid diet results
in a predominantly slow muscle becoming pure slow
muscle but with no apparent alteration of fast isoforms
in fast muscle (356). With histochemical methods, the
proportion of type I fibers in the soleus muscle changes
from 81 to 100% after 6-10 wk of the diet (356). After 7
wk of a 2% ,&guanidinopropionic acid diet, fast myosin
isoform 3 protein decreases 60% in the mouse extensor
digitorum longus muscle (276). The contractile proper-
ties of the soleus muscle exhibit a significant slowing,
whereas no change in contractile characteristics was
noted in the plantaris of the same rats after 10 wk of a
1% ,&guanidinopropionic acid diet (311). Because 6 wk
of a 1% ,&guanidinopropianic acid diet decreases cre-
atine phosphate 90% and ATP 50% in skeletal muscle
(104), one interpretation of the above studies is that a
reduction in creatine phosphate and ATP plays some
role in signaling an isoform switch from fast to slow
myosin in skeletal muscle. Likely this interpretation
needs direct confirmation at the level of the control of
gene transcription. If high-energy phosphates play a
role in signaling myosin isoform composition, then
weight bearing must have an interactive control func-
tion. When weight bearing is decreased, the phospho-
creatine level decreases and type I fiber percentage de-
creases in the soleus muscle of nonweight-bearing limbs
(146,397) and of immobilized limbs (38,262). As stated,
we speculate that multiple signals or factors from al-
tered contractile activity interact to change gene ex-
pression.
5. How adaptation alters fatigue
A switch to slow myosin heavy chain would reduce
the oxygen cost of work. The energy cost per unit force
per cross-sectional area is greater in fast than in slow
muscle (242). For a brief tetanus of t9 s, the energy cost
of the mouse fast-twitch extensor digitorum longus
muscle is 2.9 times that of the mouse soleus muscle,
which contains an equal mixture of fast and slow fibers
(73). After 9 s of tetanus, the fast muscle has only 1.5
times the normalized energy cost of that of the mouse
soleus muscle (for reviews see Refs. 242, 318). A similar
event occurs in the heart. Slow (V,) myosin is more eco-
nomical than is fast (V,) myosin (6). Thus the functional
role of the adaptive switching of myosin isoform from a
fast isoform with a high ATPase to a slow isoform with
a lower ATPase is that energy costs per unit of force
would be less after training. The reputed energy conser-
vation by the adaptive conversion to slow myosin in skel-
etal muscle is not reflected in the overall oxygen uptake,
which is unchanged at the same absolute workload in
humans after training (332). One explanation is either
that the percentage shift to slow myosin is very small in
humans or that the mass of muscle that responds by this
mechanism is small.
E. Oxygen Flux
I. Capillaries
This topic has been reviewed extensively by Saltin
and Gollnick (341). In brief, skeletal muscles in both
humans and animals adapt to aerobic training by an
increase in the number of their capillaries (341). Indeed,
training-induced increases in whole body maximal aer-
obic power are comparable to increases in the ratio of
capillaries per muscle fiber (341). Nevertheless, the
physiological significance of this adaptation is debat-
able. Saltin and Gollnick (341) conclude that the capil-
larization of skeletal muscle is not limiting to whole
body maximal aerobic power in humans. Furthermore,
they speculate on the physiological role for the adapta-
tion. Diffusion distances for gases and substrates, espe-
cially free fatty acids, would be reduced in the aerobi-
cally trained skeletal muscle (341). Saltin and Gollnick
(341) suggest that it is the decreased diffusion distance
that is the function of the increased capillarity. Re-
cently Rota et al. (330) concluded that their data were in
accord with the notion that maximal aerobic power was
the balance between convective oxygen delivery by the
blood and its subsequent diffusive movement to myofi-
brillar mitochondria through the sarcoplasm.
Increased concentrations of fibroblast growth fac-
tor were noted in skeletal muscle after 21 days of contin-
uous electrical stimulation (286). Because fibroblast
growth factor induces capillary proliferation (111) and
because continuous electrical stimulation also results in
capillary proliferation (68), it is possible that fibroblast
growth factor links increased contractile activity to an-
giogenesis in skeletal muscle. Whatever the signal that
links contractile activity with angiogenesis, the re-
sponse is rapid. As little as 4 days of electrical stimula-
tion (8 h/day) can evoke a 20% increase in capillary-to-
muscle fiber ratio (68). However, no significant increase
in fibroblast growth factor was noted after 3 days of
electrical stimulation (286).
2. Myoglobin
An adaptive increase in myoglobin concentration in
response to run training occurs in the skeletal muscles
560 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

of rats (308) but not of humans (209,378). Svendenhag et B. Animal Models Mimicking Human Heavy-
al. (378) showed that humans who trained at 75% of Resistance Training
their maximal aerobic power had no change in myoglo-
bin concentration of skeletal muscle while indicators of Animal models that closely resemble some, but not
respiratory capacity in the same muscle increased 62- all, aspects of heavy-resistance training as performed
82%. However, in rabbits, an -X-fold increase in myo- by humans have been developed. Some of these models
globin mRNA content occurs in fast-twitch muscles are described next. Mice and hamsters were trained to
after 21 days of continuous indirect electrical stimula- obtain food by pulling and holding a weighted food bas-
tion (409). These authors concluded that pretransla- ket (129-131). Although muscle fiber cross-sectional
tional mechanisms were important in establishing of area increased, muscle size was unchanged. Cats were
this adaptation (409), since myoglobin protein increased conditioned to lift weights with their right forelimb
only twofold in rat fast-twitch muscle that was chroni- against a heavy resistance to receive a food reward (139,
cally stimulated for 21 days. Thus myoglobin concentra- 140). Both an increase in muscle fiber diameter and in
tion in skeletal muscle is not altered by human physical muscle size occurred. Muscle enlarged at a rate of
activity but is increased by pretranslational mecha- O.O7%/day over 34 wk of training, which was similar to
nisms in continuously stimulated animal muscle (224). the growth rate found in humans who underwent heavy-
The role of protein degradation in these responses is resistance training.
unknown. Another animal model employed to mimic human
In a recent review, Wittenberg and Wittenberg resistance training is to electrically contract the skele-
(431) discuss the function of myoglobin. Myoglobin- tal muscles of anesthesized rats against a resistance us-
facilitated oxygen diffusion mediates a large part of the ing a training paradigm similar to the human (432). In
total oxygen flux through the sarcoplasm. In view of its these studies calf muscles are contracted against a
function, myoglobin concentrations are not limiting to heavy resistance, resulting in plantar flexion. Exercise
maximal aerobic power in humans, since aerobic power bouts are performed in sets of six repetitions/set (4 or 32
can increase in the absence of an increase in myoglobin sets/day), 2 days/wk (432). This training paradiam is
concentration (378). No explanation is available for the very similar to the repetition pattern employed in hu-
significance of the adaptive increase in myoglobin con- man resistance training. An inherent aspect of this
centration in skeletal muscles of animals that have un- model, the simultaneous recruitment of all muscle
dergone aerobic training by phasic treadmill running. fibers within a muscle (as opposed to an orderly recruit-
ment of fibers during voluntary contractions by hu-
mans), produced a serendipitous finding. Both the ankle
V. ADAPTATION OF SKELETAL MUSCLE TO REPEATED extensors and flexors in the same limb are induced to
BOUTS OF RESISTANCE EXERCISE
contract. However, the gastrocnemius muscle (ankle ex-
tensor) shortens while the antagonist tibialis anterior
muscle (ankle flexor) lengthens during active cross-
bridge formation. The response of these two fast-twitch
A. Human Physical Activity muscles differs depending on the type of training: con-
centric (shortening while contracting) or eccentric
Human regimens of heavy-resistance training gen- (lengthening while contracting). Although apparent
erally consist of intermittent bouts of low-frequency overtraining inhibits hypertrophy of the concentrically
repetitions (3-10 sets of 6-8 repetitions/set) with high trained gastrocnemius muscle, the same number of ex-
loads (67-75% of maximal voluntary contraction) and ercise repetitions produces significant hypertrophy of
long recovery periods between training bouts (2-3 days the eccentrically trained tibialis anterior muscle. A
of rest between workout days) (259). Studies in humans milder resistance training program results in similar
have been performed to observe the rates of skeletal hypertrophy of the eccentric and concentric contracted
muscle enlargement during heavy-resistance training. muscle (432).
For example, muscle cross-sectional area of elbow flex- In addition to muscle size, protein synthesis rates
ors was increased 8% after 8 wk (O.l4%/day increase) and skeletal cu-actin mRNA were determined in the ani-
and was increased 23% after 100 days (023%/day in- mal model of concentric and eccentric contraction
crease) (201). In other studies of progressive high-inten- within the same limb. Results from these studies indi-
sity resistance training by humans, arm circumference cated that alterations in translational and posttransla-
increased 11% after 5 mo (O.O?%/day increase) (262) tional control mechanisms may be as important, or
and thigh girth was 3% greater after 6 mo (O.OZ%/day more important, than pretranslational control in effect-
increase) (154). In the latter study, areas of fast-twitch ing the new size of the muscle (433, 434). For example,
fibers were increased by 27%, whereas no change in the after a single bout of either 192 concentric or eccentric
cross-sectional area of slow-twitch fibers occurred. contractions, both mixed and myofibrillar protein syn-
Thus in studies of heavy-resistance training in humans, thesis rates increase 50-60% at 12-17 h and at 36- to
muscle enlargement is relatively slow, averaging 41-h postexercise (433, 434). However, skeletal cu-actin
NO.1 % /day. mRNA and cytochrome c mRNA are not altered at these
April 1991 EXERCISE TRAINING ADAPTATIONS 561

times (433, 434). An increase in translation of protein rhythmic exercise of low resistance so that whole body
can be inferred from such data. In addition, the increase 0, uptake is increased many fold over the resting level.)
in protein synthesis rates is not necessarily associated Although hypertrophy of skeletal muscle occurs after
with muscle hypertrophy if the initial exercise bout was the onset of heavy-resistance training by humans (154,
repeated twice weekly for 10 wk. The muscle trained by 155), aerobic training does not produce hypertrophy of
concentric contraction shows no hypertrophy. Because skeletal muscle (181). Indeed, if humans combine heavy-
an earlier experiment, which employed milder resis- resistance training and aerobic training, strength devel-
tance training, resulted in 18% hypertrophy of the con- opment by skeletal muscle is usually less rapid than
centrically contracting gastrocnemius muscle (432), it with heavy-resistance training only (90, 173, 338, 339).
was speculated that the heavier resistance, the in- The decreased strength development could be due to di-
creased daily repetitions, or both may cause comparable minished recruitment of muscle fibers by central com-
increases in both protein degradation and synthesis mand (339). Although heavy-resistance training by hu-
rates in the latter report (in which no hypertrophy of mans increases the cross-sectional area of fast-twitch
the concentrically trained gastrocnemius muscle oc- fibers (391), the percentage relative area of a muscle
curred) (433). If true, a posttranslational control mecha- that is composed of fast-twitch fibers decreases in aero-
nism is present in concentric resistance training. bically trained skeletal muscle (133). Although heavy-
In contrast to the minimal effects of hypertrophy resistance training decreases the mitochondrial volume
with concentric contraction, the eccentrically trained ti- in human skeletal muscle (257, 260, 261), aerobic train-
bialis anterior muscle not only hypertrophies but en- ing increases mitochondrial volume in human skeletal
larges more when daily contractions are increased from muscle (193). Likewise, although mitochondrial enzyme
24 to 19.2 or when plantar flexion occurs against a activity per gram of skeletal muscle is unchanged (346)
greater load. If expressed for the whole tibialis anterior or decreased (390, 391) by heavy-resistance training by
muscle, increases of 41% in skeletal a-actin mRNA, of humans, it increases with aerobic training (341). Heavy-
38% in total RNA, and of 28% in protein (0.4%/day resistance training by humans either decreases, or has
increase) exist after the lo-wk program of heavy-resis- no effect, on capillary density in hypertrophied skeletal
tance eccentric training (434). These changes are even muscle (389), but aerobic training increases the capil-
more remarkable when the duration of training is cal- lary per muscle fiber ratio, capillary density, and the
culated as a percentage of the lo-wk period. Only 0.1% number of capillaries around a given muscle fiber (341).
of available time was actually spent in training eccen- These findings lead to the conclusion that molecular and
trically. This implies that the cellular and molecular cellular responses initiating adaptations are likely dif-
signals eliciting from heavy-resistance eccentric train- ferent for heavy-resistance training versus aerobic
ing are more dependent on the mechanical load than on training, since the two result in different patterns of
the contractile duration. Moreover, the -40% increase protein expression in skeletal muscle of humans.
in the muscle’s content of skeletal a-actin mRNA and in
total RNA imply that repeated applications of low-repe-
tition, high-resistance eccentric exercise is sufficient VI. HYPERTROPHY IN ANIMAL MODELS NOT MIMICKING
to upregulate pretranslational control mechanisms. HUMAN PHYSICAL ACTIVITY
On the other hand, the heavy-resistance concentric
training program does not increase skeletal a-actin
mRNA (434). A. Adaptations Difler Between Certain Animal Models
The differential responses to concentric and eccen- and Humans
tric resistance training in the rat model of human train-
ing emphasize that multiple control sites (pretransla- Some of the adaptive protein expression occurring
tional, translational, and posttranslational) can be elic- in animal models of skeletal muscle hypertrophy are not
ited during training. Future interpretations of similar to the adaptations that occur in human skeletal
mechanisms of muscle hypertrophy in animal models muscle after heavy-resistanc.e training. Thus these ani-
should only be related to the human sport that it mim- mal models are classified as not mimicking the human
ics, since various types of resistance training in rats give sport of resistance training. For example, significant
different combinations of pretranslational, transla- hypertrophy of skeletal muscle does not occur for 2 mo
tional, and posttranslational control. in humans undergoing heavy-resistance training (401),
but significant hypertrophy of skeletal muscle occurs
within days of the onset of continuous stretch and of
C. Adaptations Difer in Aerobic and Strength Training continuous overload of rat or chicken muscles (123,249).
Mitochondrial volume density decreases in human skele-
Programs of aerobic training and of heavy-resis- tal muscle during heavy-resistance training (257, 260,
tance training by humans result in different adaptive 261), but mitochondrial enzymes rapidly increase in the
changes in the structure and function of skeletal muscle, stretched hypertrophying fast-twitch muscle of the
some of which are contrasted next. (Aerobic training is chicken wing (97,186). In addition, the percentage of the
the involvement of large masses of skeletal muscle in total cross-sectional area that is composed of fast-
562 FRANK W. BOOTH AND
twitch fibers increases in human skeletal muscle after
chronic heavy-resistance training (389,390), but the per-
centage of the muscle cross section that is composed of
fast-twitch fibers decreases in the animal models of con-
tinuous stretch and of continuous overload (147, 199,
210). Increases in fiber diameter of both fast- and slow-
twitch fibers often occurs in human skeletal muscle
after heavy-resistance training (261). Magnesium-stim-
ulated myofibrillar ATPase activity decreases in human
skeletal muscle after 6 mo of heavy-resistance training
(390), so it is possible that slow myosin isoforms in-
crease in fast-twitch muscle with 6 mo of heavy-resis-
tance training. A definite shift from fast to slow myosin
heavy chain occurs in continuous stretch (186) and in
continuous overload (406).
B. Animal Models of Stretch-Induced Hypertrophy
I. Description
Those models that chronically stretch a muscle pro-
duce a muscle hypertrophy that occurs much more rap-
idly than that produced by a human undergoing a pro-
gram of heavy-resistance training. “Stretch” can be
produced by any one of numerous models, some of which
give different adaptive changes in the hypertrophying
muscle. In 1944, Thomsen and Luco (400) reported that
when the ankle joint of a cat was immobilized in dorsi-
flexion for 14 days, there was an increase in the weight
of the stretched soleus muscle and a decrease in the
weight of the shortened tibialis anterior muscle. Con-
versely, fixation of the joint in plantar-flexion reversed
the effects, i.e., the soleus muscle atrophied and the ti-
bialis anterior muscle hypertrophied. These authors in-
terpreted their results to suggest that the degree of ten-
sion, or stretch, to which the muscle was exposed during
joint fixation determined the adaptive new size of the
muscle. In later work it was determined that muscle
enlargement occurs by the addition of sarcomeres
in series (421) without any increase in muscle fiber diam-
eter (368).
In 1953, transient hypertrophy of the denervated
side of the diaphragm was reported (365). This finding
was attributed to chronic, periodic stretching of the de-
nervated fibers by contractions of the still functional
and periodically contracting contralateral hemi-
diaphragm (149,365). Transient increases both in mus-
cle size and in total RNA were noted. Even though after
7 days of denervation the denervated side of the dia-
phragm was 55% larger with 74% more RNA, by day 40
of denervation the denervated muscle size had regressed
to control values and RNA was only 50% of control (40).
Increases in protein synthesis rate of 41,94,43, and 33%
have been reported for the denervated hemidiaphragm
at 1,3,5, and IO days, respectively (408). Protein degra-
dation rates are increased by 55% on day 1 and by
-156% on days 3-7 on the denervated side of the dia-
phragm. Thus although this model further emphasizes a
DONALD B. THOMASON Volume 71
role of stretch in the induction of muscle hypertrophy,
its shortcoming is the transient nature, since hyper-
trophy in human skeletal is not transient during heavy-
resistance training programs.
Some earlier shortcomings were remedied by the
model of stretching the slow-twitch chicken anterior la-
tissimus dorsi (ALD) muscle. Feng et al. (102) first
showed that, on its denervation, the ALD muscle under-
goes permanent hypertrophy. Later it was deduced that
the weight of the denervated wing is the causal factor
for the hypertrophy. Supporting this deduction is the
observation that attaching additional weights to the de-
nervated wing produces a more rapid and greater hy-
pertrophy than produced by denervation alone (364).
These investigators concluded that stretch is the stimu-
lus for growth. Furthermore, they observed the same
effect in the innervated ALD muscle. It is also clear that
the biochemical adaptations that occur in chronically
stretched skeletal muscle are specific to the initial fiber
type of the muscle. It must be further emphasized that
stretch is not the only stimulus that can generate en-
largement of muscle. As mentioned, active mechanical
forces also induce muscle enlargement.
2. Adaptive changes in protein expression
Adaptive increases in the mass of the chicken slow-
twitch ALD muscle are associated with a switch to a
slower myosin isoform, without any change in mito-
chondrial density (186). With growth of the ALD muscle
as the normal chicken grows older, there is a develop-
mentally regulated gene switch; the expression of the
slow myosin 1 heavy-chain gene is repressed while the
slow myosin 2 heavy-chain gene expression is induced.
By the attachment of a weight to the wing of 5-wk-old
chickens, the switch from slow myosin 1 to slow myosin
2 heavy chain is accelerated (227). The appearance of
slow myosin 2 during development is closely correlated
with the slowing of the maximal velocity of shorten-
ing (320).
Continuous stretch of fast-twitch muscle produces
different types of adaptations than those described for
the effects on continuous stretch on the ALD muscle.
Some of the adaptations in continuously stretched fast
muscle are as follows. The percentage increase and the
duration of the increase in protein synthesis rate are
smaller in continuously stretched fast than slow muscle
(249). Mitochondrial density increases in continuously
stretched fast muscle (148). Activity of citrate synthase
increases 100% and oxidation of succinate increases
174% in fast-twitch muscle that is stretched for 5 wk
(186). The same muscles double in mass for this duration
of stretching. The activity of &aminolevulinate syn-
thase, the rate-limiting enzyme for heme synthesis, pre-
cedes the increase in the activity of cytochrome-c oxi-
dase, an enzyme containing heme in continuously
stretched fast-twitch muscle. After 3 days of stretch, no
change in cytochrome-c oxidase activity is detected,
whereas a 150% increase in &aminolevulinate synthase
April 1991 EXERCISE
activitv and a 60% increase in the mRNA for b-aminole-
vulinate synthase occurs (97). Essig et al. (97) suggested
that both pretranslation and either translation or post-
translation effects, or both, increase b-aminolevulinate
synthase activity during stretch of a fast-twitch muscle.
3. Protein synthesis and degradation
When a weight is chronically attached to the wing
of a chicken, a 140% increase in protein content occurs
in the slow-twitch ALD muscle (249). The increase in
muscle protein synthesis rate exceeds the increase in
muscle protein degradation rate. As shown in Figure 3,
20% of the increase in the protein synthesis rate ac-
counts for net muscle growth while 80% of the increased
synthesis contributes to an increased turnover of pro-
teins. Increased protein degradation would be classified
as a posttranslational control. An increase in protein
translation occurs on day I followed by an increase in
RNA quantity on day 3 so that the ratio of protein syn-
thesis per unit of RNA returns to normal at this time
(249). Because -80% of RNA is rRNA, the assumption
was made that measurements of RNA approximated
rRNA quantity. Therefore an increase in the pretrans-
lational control occurs by day 3 of the stretch. When the
ALD muscle is stretched, a large increase in the subsar-
colemmal concentration of myosin heavy-chain mRNA
occurs in the region of these rapidly growing fibers (94).
Deoxyribonucleic acid quantity doubles in the hypertro-
phying ALD muscle, and Laurent et al. (249) deduced
that this is likely satellite cell proliferation and incorpo-
ration into muscle fibers. This deduction has been con-
firmed with three observations in the 1st wk of the
chronically stretched ALD muscle (226). First, there is
an increase in close contact between satellite cells and
the sarcolemma. Second, the volume and surface area of
-4Or
10 20 30 40 50 60
t Days of Hypertrophy
wemht
add-&d
FIG. 3. Calculated percentage rate of protein synthesis as func-
tion of time after initiation of constant stimulus (weight added) for
hypertrophy of fast-twitch muscle. During growth period, increase in
protein synthesis rate over control (normal replacement) is shown.
Majority of increase in protein synthesis does not contribute to
growth but is involved in remodeling (wastage). [From Millward
w-5).1
TRAINING ADAPTATIONS 563
the satellite cells triples. Third, satellite cell number
increases.
The myotendinous junction of a continuously
stretched fast-twitch muscle in rabbits is a site of accu-
mulation of slow myosin heavy-chain mRNA (83). Dix
and Eisenberg (83) speculate that increased slow myo-
sin heavy-chain mRNA at the myotendinous junction
would contribute to an increase in regional protein syn-
thesis and myofibril assembly at this site (83). A large
cytoplasmic space that was devoid of myofibrils formed
at the myotendinous junction. The sequence of myofibril
assembly in this model was found to be that actin fila-
ments attached in part to vinculin on the tendon and
sarcolemma. Thick contractile filaments join the thin
filaments. Z-bodies then assemble with the thick and
think filaments setting the sarcomeric register (83).
The above observations have been extended by
Gregory et al. (143) in a report on the synthesis rates of
individual contractile proteins and mRNA levels during
overload hypertrophy of the chicken ALD muscle. Total
protein synthesis rates double at 24 h of overload with
no change in polyadenylated mRNA quantity. An in-
crease in translation is inferred. Actin protein synthesis
rates double at 24 h and triple at 72 h of overload. In
contrast the protein synthesis rates of slow myosin 1
and of slow myosin 2 decrease at 24 h and then increase
at 72 h of overload. Because slow myosin 2 replaces slow
myosin 1, a selective degradation of slow myosin 1 was
inferred. In addition, the relative quantity of slow myo-
sin 1 mRNA decreases even though its absolute protein
synthesis rate appears unchanged. These data support
the concept that the response of synthesis rates of indi-
vidual proteins differ among proteins. If true, measure-
ment of changes in the synthesis rate of mixed proteins
may be misleading for certain specific proteins.
C. Animal Models of Compensatory Overload-Induced
Hypertrophy
1. Protein synthesis and degradation
Another model used for studying adaptive changes
to increased usage is compensatory hypertrophy of skel-
etal muscle. The workload of selected muscles are in-
creased by either tenotomy of synergistic muscles or ab-
lation of some of the synergistic muscle (12,19,123). An
increase in protein synthesis rate has been shown to
account for net protein gain in skeletal muscles under-
going compensatory hypertrophy (124,158). Excess pro-
tein is likely being synthesized because the fractional
rate of protein degradation increases 73% in fast-twitch
muscle during the 3rd-7th day of its compensatory hy-
pertrophy (272). Most of the increase is blocked by fen-
bufen, a prostaglandin inhibitor (272).
2. Ribonucleic acid and deoxyribonucleic acid
Ribonucleic acid concentration increases in skeletal
muscles undergoing compensatory hypertrophy (124,
564 FRANK W. BOOTH AND DONALD B. THOMASON Volume ?I

158). This increase in RNA appears to be essential to the pertrophy of the plantaris muscle, whereas increases of
muscle growth, because treatment of rats with actino- 310 and 450%) respectively, occur at the 11th wk of plan-
mycin D prevents the compensatory hypertrophy (125, taris muscle hypertrophy (310). In the same muscle,
127). An increased synthesis of RNA in vivo is detect- there is an approximate parallel increase of 50% in fast
able within 24 h after initiating the compensatory hy- IIa myosin heavy-chain mRNA and its protein and an
pertrophy (363). An increase in RNA polymerase quan- -50% decrease both in fast IIb myosin heavy-chain
tity in isolated nuclei in vitro occurs on the 3rd day, but mRNA and its protein. The report attributed the in-
not the 1st or 2nd day, of compensatory hypertrophy crease in fast IIa myosin as an intermediate step in the
(363). Sobel and Kaufman (363) interpret their observa- conversion of fast to slow myosin (310). Changes in ,&
tions to mean that an increase in the activity of RNA slow myosin heavy chain mRNA do not occur in the first
polymerase occurs in vivo on day 1, whereas the quan- 7 days of compensatory hypertrophy in the plantaris but
tity of RNA polymerase increases by day 3 (363). Fur- increase at day IO (70). The increase in mRNA seems to
thermore, they suggest that RNA polymerase I (rRNA) precede the increase in ,&slow myosin heavy-chain
and II (mRNA) both increase on day 3. However, it was protein (70). Thus pretranslational control appears to
later demonstrated that proliferating capillaries and fi- be the exclusive control of isoform switching of myo-
broblasts are the major site of the new RNA synthesis sin heavy chain during compensatory hypertrophy in
in skeletal muscle undergoing compensatory hyper- the rat.
trophy (205). Furthermore, this increase was found to Likewise, the decrease in phosphorylase expression
occur only in the distal portion of the hypertrophying in the plantaris muscle during compensatory hyper-
soleus muscle. A 30% increase in DNA per whole muscle trophy appears to be totally a result of pretranslational
has been observed on the 4th day of compensatory hy- control, because both phosphorylase mRNA and enzyme
pertrophy (158). Some of this DNA increase must be activity decrease in parallel (70). However, in contrast
from satellite cell proliferation, as the number of satel- to the more delayed onset of myosin heavy-chain iso-
lite cells increases from 5.8 to 16.6% in the 7th day of form switching, the decrease in phosphorylase mRNA is
compensatory hypertrophy by soleus muscle (159). complete by the 2nd day of compensatory hypertrophy
of the plantaris muscle (70). Crerar et al. (70) concluded
that these two genes, ,&slow myosin heavy chain and
3. Myosin isoforms phosphorylase, are “discoordinately regulated” in this
model of hypertrophy.
Tsika et al. (406) showed an increase of fast IIa
myosin heavy-chain protein along with the increase in 5. Shortcomings
slow myosin heavy-chain protein during continuous
overload hypertrophy of the plantaris muscle. Func- A number of the responses and adaptations of mus-
tional overload of the plantaris muscle of rats, which is cle during compensatory hypertrophy are unusual. The
caused by removal of synergist muscles, results in the initial 40% increase in the wet weight of the plantaris
slow myosin isoform increasing from 4.3 to 18.3% of muscle is due, in part, to edema, connective tissue prolif-
myosin after 6 wk of the overload (406). Tsika et al. (406) eration, and cells involved in tissue repair (12,198,225).
interpreted their results to suggest that the slow myosin Both edema and leukocyte invasion peak at the 4th day
isoform can be expressed in increased quantities in fast- of compensatory hypertrophy of the plantaris muscle.
twitch muscle if the weight-bearing function is trans- Thereafter, protein accumulation and increases in mus-
ferred from the slow soleus muscle to the fast plantaris cle wet weight parallel each other. Crerar et al. (70) spec-
muscle. Thus mechanical stress has a significant impact ulated that a transient 70% decrease in ,&slow myosin
on the expression of slow myosin in rat skeletal muscle; heavy-chain mRNA on the 2nd day of compensatory hy-
this conclusion is in agreement with the results from pertrophy is related to “surgical trauma.” During
decreased weight-bearing experiments (sect. IVD3). chronic compensatory hypertrophy of the plantaris
muscle, a decrease in maximum isometric tetanic ten-
sion per unit of cross-sectional area occurs (334). Thus,
4. Messenger ribonucleic acids
as stated by Gutmann et al. (150) in 1971, compensatory
hypertrophy of skeletal muscle represents a reaction to
Extensive evidence exists that myosin isoform ex- functional overload that is of doubtful adaptational
pression is shifted from fast to slow during compensa- value because of the decrease in maximum isometric
tory overload, particularly in fast muscles (15, 19, 147, tension per unit of cross-sectional area of the hypertro-
199,406). For the most part, a parallel increase occurs in phied muscle.
slow myosin heavy-chain mRNA, ,&slow myosin heavy-
chain protein, and the percentage of slow-twitch fibers
in the plantaris muscle during O-31 days of compensa- VII. MUSCLES OR MUSCLE CELLS IN CULTURE DO NOT
tory hypertrophy (70). A similar parallelism was re- MIMIC HUMAN PHYSICAL ACTIVITY
ported in a study from another group. The ,&slow myo-
sin heavy chain mRNA and its protein increase 235 and Numerous reports exist in which organ or tissue
130%, respectively, at the 4th wk of compensatory hy- culture was employed for the purpose of determining
April 1991 EXERCISE TRAINING ADAPTATIONS 565

the chemical linkage between stretch and muscle hyper- Another prostaglandin synthesis inhibitor, fenbufen,
trophy. An excellent critical review of this area was re- does not prevent compensatory hypertrophy in rats but
cently published by Vandenburgh (411). Only selected lessens the increase in protein synthesis rates at the 7th
topics are repeated here. The reader is referred to that day of hypertrophy (272). No role was found for prosta-
review for a more comprehensive treatment. glandins as a causal factor in the acute stimulation of
Shortcomings of most organ culture systems are protein synthesis in the heart by hypertensive aortic
that skeletal muscles in vitro are in a negative nitrogen pressures or insulin in vivo (361).
balance (118,411) and that organ cultures are not viable Although one report found that the calcium iono-
long enough to produce hypertrophy. For example, dur- phore A23187 increases protein synthesis rates in incu-
ing incubation of the rat diaphragm in unsupplemented bated skeletal muscles (219), two later studies have not
Krebs Ringer buffer, the net rate of protein degradation observed an effect (331,361). Thus increased sarcoplas-
is Z-Z.5 times greater than the rate of protein synthesis mic free Ca2’ may not link increased contractile activity
(118). It is possible that mechanisms controlling protein to increases in protein synthesis in skeletal muscle. On
synthesis and degradation differ from in vivo mecha- the other hand, increased free Ca2’ has been shown to
nisms when such large differences in protein balance increase protein degradation in skeletal muscle in vitro
exist. Therefore effects of stretch may be acting though (219). It is clear that muscle hypertrophy is associated
different mechanisms than present in vivo. However, with an increased protein degradation (249). A potential
under selected experimental conditions, nitrogen bal- consequence of increased free Ca2’ is membrane dam-
ance can be made to zero in the incubated fast-twitch age. Vitamin E has been shown to inhibit the efflux of
epitrochlearis muscle (374). creatine kinase from A23187-treated skeletal muscle in
In contrast to whole muscles, Vandenburgh (411) vitro (313). Phoenix et al. (313) suggested that vitamin E
indicated that primary cultures of skeletal muscle cells inhibits the muscle sarcolemmal changes induced by in-
provide an advantage over whole muscle cultures, be- tracellular Ca2+ overload, which, in the absence of vita-
cause cultures of muscle cells can be maintained in a min E, causes intracellular enzyme efflux (313).
condition of positive nitrogen balance for weeks. More-
over, mechanical stretching of embryonic chicken skele-
tal myotubes while they are cultured leads to an in- VIII. REGROWTH OF ATROPHIED SKELETAL MUSCLE
creased accumulation of total protein and myosin heavy
chains (412). A shortcoming of cultured muscle cells is Multiple sites controlling gene expression are in-
that often they do not express slow myosin or adult iso- voked in the early period of recovery from muscle atro-
forms. Also cultured cells cannot mimic the mechanical phy, before demonstrable muscle enlargement. Protein
loading existent in human sport, nor do they experience content of fast-twitch muscle decreases 27% during 7
the hormonal and neural environment of muscle in hu- days of limb fixation in a shortened position in rats
man physical activity. (407). During the initial 4 days of recovery from the
Stretch of either cultured whole muscle or muscle ‘I-day immobilization, muscle weight does not increase
cells results in an increased rate of protein synthesis (37). Nevertheless, actin protein synthesis rate, which is
(23,41,48,126,300,301,412). Cultured skeletal myotubes 33% of the control level at the 7th day of hindlimb im-
respond to passive stretch by a 60-70% increase in the mobilization, returns to the control value on the 2nd day
Vmaxof the sodium pump (413). No increase in the num- of recovery and is three times higher than control in the
ber of sodium pumps was detected. Ouabain prevents fast-twitch muscle on the 4th recovery day after limb
the stretch-induced increase in protein synthesis (413). immobilization in rats (285). During the recovery, rats
Vandenburgh and Kaufman (413) suggested that so- were permitted cage activity. The skeletal cw-actin
dium pump activation may be involved in the stretch-in- mRNA is 53% of control at the 7th day of limb immobi-
duced cell growth of cultured cells. On the other hand, lization, and its increase during the first 2 recovery days
tetrodotoxin inhibits voltage-dependent sodium chan- parallels the increase in actin synthesis rate; this sug-
nels and spontaneous activity but does not prevent the gests that pretranslational mechanisms are the cause of
increases in either the protein synthesis rate or in pro- the initial increase in actin protein synthesis rate in
tein accumulation that occurs when muscle cells are fast-twitch muscle recovering from atrophy (285). How-
stretched in culture (412). ever, further increases in actin synthesis from the 2nd-
It has been suggested that stretch of whole muscles 4th day appear to be under translational control, since
increases prostaglandin synthesis by the muscle, which actin protein synthesis rate is 300% of control on the 4th
in turn increases muscle protein synthesis (361). Prosta- recovery day, but skeletal cu-actin mRNA is only 128% of
glandin secretion into the culture medium increases in control (285). Because muscle protein mass is un-
mechanically stimulated muscle cells (163). Both indo- changed, this suggests an increased remodeling (in-
methacin and meclofenamic acid, which are prostaglan- creased protein degradation). Thus in the initial phases
din synthesis inhibitors, decrease the rate of protein syn- of recovery as fast-twitch muscle prepares to regrow
thesis in intermittently stretched muscles in vitro (361). from atrophy, pretranslational, translational, and post-
An earlier report from the same laboratory indicated translational mechanisms for skeletal cu-actin gene ex-
that muscles incubated under control conditions have a pression are invoked.
protein synthesis rate that is 22% of those found in vivo. The recovery of cytochrome c gene expression from
566 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

7 days of limb immobilization has a somewhat different X. ADAPTATIONS THAT AFFECT CARDIAC OUTPUT
time course (284). During the first 2 days of recovery,
cytochrome c protein synthesis rate and cytochrome c The molecular and cellular adaptations of the car-
mRNA were maintained at the low levels found at the diovascular system to exercise training are considered,
start of recovery from muscle atrophy caused by 7 days as they ultimately affect the capacity to deliver oxygen
of hindlimb immobilization in rats (284). However, at and nutrients. The data must be viewed with the bias
the 4th recovery day, cytochrome c protein synthesis that the adaptations, if important, affect the economy
rate is 192% of control while cytochrome c mRNA is of delivery. This is an underlying premise of adaptation.
126% of control. Because the percentage increase in cy- Therefore the adaptations are considered as they affect
tochrome c protein synthesis is greater than the percent- the minute work of the heart within the entire cardio-
age increase in cytochrome c mRNA, it is likely that vascular system: heart minute work = heart rate x
both pretranslational and translational mechanisms stroke volume X pressure. To provide a more efficient
are invoked in as muscle begins to recover from atrophy. delivery of oxygen and nutrients during exercise, the
exercise training adaptations of the cardiovascular sys-
tem are viewed with the inclination that pressure in-
creases are minimized in favor of adaptations that pro-
IX. SUMMARY OF INFERRED SITES FOR GENE vide an enhanced stroke volume. This supposition is
EXPRESSION IN THOSE ANIMAL MODELS THAT based on the tenet that changing the work of the heart
CLOSELY MIMIC HUMAN PHYSICAL ACTIVITY by changing volume is energetically more efficient than
by changing pressure (98). Although the adaptation of
the cardiovascular system to exercise training has been
To make a general conclusion about the potential extensively reviewed (35, 348), significant advances
sites of gene expression in skeletal muscle where altered have been made in the tools and concepts with which to
muscle usage produces a change in protein quantity, approach the molecular and cellular mechanisms of ad-
three different proteins, the quantities of which are al- aptation.
tered in four animal models of various human physical The cardiovascular system is extremely responsive
activities are shown in Table 3. to functional demand on a beat-to-beat basis, often
The composite of the data leads to the next conclu- maintaining function by drawing on one mechanism to
sion. Multiple sites (pretranslational, translational, and compensate for another that has been compromised.
posttranslational) are inferred to be evoked as protein This intrinsic responsiveness often makes it difficult to
quantities adapt to new steady-state levels because of definitively single out one factor or mechanism responsi-
chronic changes in muscle usage. Such an analysis sug- ble for a particular adaptation. For example, during
gests that the control of gene expression in skeletal adrenergic ,&receptor blockade in humans, maximal car-
muscle during chronic changes in human physical activ- diac output is maintained, despite a reduced heart rate,
ity is very complex. It is likely that most, if not all, of the by an increase in stroke volume (32). Another example
following are altered: gene transcription, mRNA stabil- occurs during exhaustive exercise. Cardiovascular drift,
ity, protein translation, protein assembly, and protein i.e., a progressive decrease of systolic pressure and
degradation. If true, this means that efforts to delineate stroke volume, is compensated by increasing heart rate,
all mechanisms by which human physical activity pro- resulting in no net change in work (278). With this com-
duces adaptive changes in protein quantity will require pensating ability as a potential complication to inter-
more research time than envisioned a decade ago. pretion, the cellular and molecular adaptations to exer-

TABLE 3. Inferred or directly measured sites of altered gene expression in skeletal muscle of adult rats

Activity Model Protein Pretranslational Translational Posttranslational

Nonweight bearing Actin X X X

Myosin heavy chain X X X
Recovery from atrophy Actin X X X
e
Cytochrome c X X X
cl
Run training Actin X
Cytochrome c X X
cl
Resistance training Actin X X X
Cytochrome c X X X
El
rRNA clX

X, Site is affected; x , inferred as first site of temporal regulation.

II
April 1991 EXERCISE TRAINING ADAPTATIONS 567

cise training that affect cardiac output are considered A

next. They fall into the two broad categories of stroke
volume and chronotropic adaptations.

cardiac
A. Stroke Volume Adaptations trained
function

The stroke volume adaptations to exercise training

can be further subdivided into those that alter stroke
volume by the Frank-Starling mechanism and those
that alter ejection volume through changes in contractil-
ity (inotropic adaptations). In the untrained individual
exercising at relatively low work loads, the Frank-Star- 0
ling mechanism is the most important factor for main- Right Atrial Pressure
taining cardiac output; at near maximal work loads,
where end-diastolic volume cannot be further increased, B
an increase in ejection fraction is necessary for an in-
crease in cardiac output (175). These mechanisms for vasodilation
providing sufficient cardiac output to maintain a given
work load are modified and enhanced as a result of cardiac
training. For example, in sprint-trained rats, cardiac function
output can be maintained at a greater level than in the
sedentary animal despite a lower or comparable heart
rate due to an increased stroke volume (121,176). Next,
some of the mechanisms whereby exercise training
alters the Frank-Starling and inotropic mechanisms for.
maintaining cardiac output are explored.
0
Right Atrial Pressure
I. End-diastolic volume: Frank-Starling mechanism
C
1)ADAPTATIONSTHATAUGMENTVENOUSRETURN
ORINCREASE CENTRALBLOODVOLUME. A)Homeostatic vasodilation enhanced
mechanisms. Exercise training increases the plasma contractility
and blood volumes in humans as a result of adjustments 3a cardiac
in fluid conservation (69,115,161,298). The expansion of 5 function
blood volume serves to increase mean circulatory filling 0
pressure (228) either directly or by autoinfusion during 0m
exercise, thus augmenting cardiac output by the Frank-
Starling mechanism (Fig. 4A). We examine some of the
mechanisms involved in fluid conservation as reflected
in those hormones responsible for electrolyte and water
balance. 0 0
Despite the increase in blood volume and the lower Right Atrial Pressure
mean arterial pressure that are nominally found in en-
4., At given level of exertion, cardiac output is equilibrium
FIG. of
durance-trained subjects, at rest atria1 natriuretic pep- vascular function and cardiac function. A: as result of training, in-
tide (ANP), plasma renin activity (PRA), antidiuretic creased blood volume in endurance-trained subjects would shift equi-
hormone (ADH or vasopressin), and aldosterone levels librium point on cardiac function curve to greater potential cardiac
are not different from the untrained individual (115, output. This response is similar to effect of transfusion. B: given in-
116,415). Therefore resting levels of these factors do not creased blood volume in trained individual, vasodilation (decreased
peripheral resistance) would augment venous return and shift equilib-
explain the increase in blood volume. To determine if rium point further up cardiac function curve. C: in addition to effects
there is a difference in the ability of trained and un- of increased blood volume and decreased peripheral resistance in
trained subjects to handle a water load, Freund et al. trained individual, an increase in cardiac contractility would further
(115) examined the plasma levels of these hormones increase cardiac output.
after water ingestion. They found that water ingestion
does not differentially affect ANP, PRA, or aldosterone
in the endurance-trained subjects (runners) compared creases, whereas the plasma ADH decrease of the
with untrained control subjects. However, the plasma trained individuals is blunted (115). The fact that there
ADH level in the untrained individuals significantly de- is no difference in the change in plasma volume and
568 FRANK W. BOOTH AND
there is a similar decrease in plasma osmolality in the
trained and untrained subjects in response to an in-
gested water load (115) indicates a decrease in sensitiv-
ity of the osmoreceptors in trained individuals. This is
in contrast to a previous study that indicated an in-
crease in plasma ADH levels because, in response to
water load or whole body immersion, endurance-trained
individuals (runners and swimmers) exhibit a greater
ADH excretion (63) despite an apparent decrease in the
glomerular filtration rate in trained individual [as esti-
mated from creatinine clearance (115)]. Thus there ap-
pears to be some uncertainty about the response of ADH
as a possible mediator of the increased plasma volume
in athletes. To add to this uncertainty is the observation
that during exercise, despite the lack of a difference in
plasma ADH levels between trained and untrained indi-
viduals exercising at the same relative work load or at
maximum work load, plasma ADH levels are lower than
in the trained individual at the same absolute work load
(66, 415). This adaptation in ADH response would lead
to an increase in free-water clearance in the trained indi-
viduals. In further contrast is the observation that
trained subjects exhibit a decreased plasma osmolality,
perhaps as a result of increased sensitivity of osmore-
ceptors (114). This finding is clearly in conflict with the
apparently blunted osmoresponse to water challenge
just mentioned. On the basis of these data, we can only
conclude that the ADH response and osmoreceptor adap-
tation to exercise training remains an open question.
Exercise itself stimulates the renin-angiotensin-al-
dosterone axis, setting into motion a means by which
fluid conservation can occur. However, aerobic training
has no differential effect on the renin-angiotensin-al-
dosterone axis response to exercise in endurance-.
trained versus untrained individuals, except that
trained individuals exhibit an attenuated PRA level at
90 % vo, max(256). Although a diminished PRA level rel-
ative to control would apparently work against fluid
conservation, adaptation to the training apparently also
occurs at the level of the adrenal glomerulosa cell be-
cause, during the exercise, the increased aldosterone
level is not correlated with its known regulatory sub-
stances (256). On the other hand, Hespel et al. (172)
found a slight nonsignificant depression of the renin-
angiotensin-aldosterone axis with endurance training
but observed that the decrease in these substances was
negatively correlated with the increase in work capacity
after training. Therefore the greatest depression of the
renin-angiotensin-aldosterone axis occurs in those indi-
viduals on whom training has the greatest effect (172).
An exciting development within the past decade
with regard to fluid homeostasis has been the character-
ization of ANP. The effects of ANP are somewhat mixed
and even counterintuitive with regard to exercise train-,
ing adaptation. It is worthwhile to briefly review the
putative mechanisms by which ANP secretion is regu-
lated. The causative factors involved in ANP release are
primarily related to changes in atria1 pressure. Mea-
sures that increase central blood volume increase ANP
release (87). whereas a decreased blood volume does not
DONALD B. THOMASON Volume 71
change ANP levels (178). Increasing the mean arterial
pressure appears to be a stimulus for ANP release (293,
335), although the suggestion has been made that heart
rate may also be influential (337). However, cardiac pac-
ing in dogs does not change ANP levels, whereas in-
creased atria1 pressure does cause ANP release (417).
The actual cellular mechanism by that atria1 cells are
stimulated to secrete ANP in response to changes in
pressure or stretch has yet to be fully defined. Prevent-
ing cultured rat atria1 myocytes from contracting re-
duces the secretion of ANP in a manner that apparently
is not dependent on calcium; nevertheless, ANP secre-
tion is stimulated by phorbol ester, indicative of a pro-
tein kinase C-mediated stimulus (200). Increased sym-
pathoadrenal activity may also contribute to ANP se-
cretion (392) as discussed below.
How then could a factor known to induce natriure-
sis contribute to an overall improvement of cardiovascu-
lar function after exercise training? In addition to the
natriuretic effect of the peptide, infusion of physiologi-
cal doses of ANP into a normal individual causes arte-
rial vasodilation and a decreased total peripheral vascu-
lar resistance (34,49). In untrained individuals this re-
sults in decreased cardiac output as a result of decreased
venous filling pressure (122), but in the trained individ-
ual with sufficient vascular reserve, this would have the
net effect of shifting toward greater cardiac output on
the cardiac function curve. Atria1 natriuretic peptide
also inhibits the secretion of aldosterone, although at
plasma concentrations that may exceed those normally
found (3). One possible mechanism for this response is a
differential effect of ANP on the voltage-sensitive Ca2+
channels of the glomerulosa cells, inhibiting the Ca2’
current derived from T-type channels (258). These non-
natriuretic consequences of ANP action may play the
more important role in the exercise training adaptation,
because ANP levels do not indicate a blunted natriure-
sis. Resting levels of ANP are similar in both trained
and untrained individuals, although glomerular filtra-
tion rate is lower in the endurance-trained subject (115),
perhaps diminishing the potential for natriuresis. Fur-
thermore, ANP levels increase with various exercise reg-
imen (116), but ANP levels increase more during exer-
cise in subjects receiving ,&adrenoreceptor blockade
(393). This suggests an influence of sympathetic drive
(which is depressed in trained individuals) on the inhibi-
tion of ANP release. Thus, although it is difficult to see
how natriuresis as a result of ANP release could aug-
ment venous return, the secondary effects of ANP may
be more important to the trained individual. This is cer-
tainly an area that deserves further research.
B) Vascular tone. Although the concept of the “mus-
cle pump” as an important factor in augmenting flow to
the venous side of the circulatory system has been un-
derstood for over 40 years (315), little attention has been
given to potential adaptations that can occur at the level
of the arteriolar musculature to augment flow to exer-
cising muscle. Such adaptations could serve to enhance
the muscle pump in a manner analogous to the enhance-
ment of cardiac output bv an increased venous return.
April 1991 EXERCISE TRAINING ADAPTATIONS 569

Several lines of evidence suggest that exercise training data from swim-trained rats. ,&Adrenergic receptor
adaptations in vascular tone do occur, although the density on the myocardium of these animals does not
mechanisms for the adaptation remain to be explained. change, suggesting that the site of action is not ,&adren-
Using microspheres, Armstrong and Laughlin (IO) dem- ergic receptors (426). However, there is a decreased
onstrated that blood flow to exercising endurance- myocardial cholinergic and a-adrenergic receptor den-
trained muscle is greater than in control animals. The sity in swim-trained rats, but the significance of these
fact that this muscle is working and acts as a muscle changes is unknown (426). The mechanism of exercise
pump would augment venous return (245). Further evi- training-induced bradycardia is discussed more fully in
dence of an adaptation in arteriolar tone with exercise section XB.
training is the decreased total peripheral vascular resis-
tance observed during recovery from exercise in trained
subjects (76). Central to the mechanism of the adapta- 2. Ejection fraction (size and contractility)
tion that affects arteriolar tone is the training-induced
attenuation of central baroreflex function. In treadmill- In addition to the changes in cardiac output that
trained rabbits, experimentally induced inhibition of occur as a result of changes in stroke volume by the
cardiac afferent nerve activity results in a normal renal Frank-Starling mechanism, it is possible that the frac-
sympathetic nerve response to changes in pressure, tion of blood ejected during each stroke can be changed
ameliorating the attenuated response observed after by adaptations in contractility and functional mass of
training (77, 78). Exercise training in rabbits also en- the ventricles. These adaptations, because they occur at
hances blood flow to the renal and mesenteric arteries the cellular level, are often difficult to detect function-
through an increased inhibitory effect of the cardiac ally. For example, in pigs trained by treadmill running
vagal afferents on the exercise-induced increase in vas- for 10 wk, no adaptations were observed in one study
cular resistance of these arteries, as determined by where contractility was assessed by measurement of
blockade of cardiac efferent nerve activity (79). Thus ventricular dimensions and left ventricular change in
baroreceptor function apparently adapts with exercise pressure over time (420). On the other hand, in humans,
training (151) such that greater blood flow is main- stroke volume is greater at all levels of upright exercise
tained in nonworking organs, a phenomenon that is one as a result of training (382). This may be a unique but
of the hallmarks of endurance exercise training (332). necessary adaptation in humans because, despite an in-
This attenuated baroreceptor response may also contrib- crease in venous filling pressure, end-diastolic volume
ute to the increased plasma volume by decreasing the decreases and thus an increase in stroke volume is
renal vascular response, i.e., attenuated sympathetic needed to maintain cardiac output during upright exer-
nerve activity to increased blood pressure during the cise (175). Therefore, as discussed next, assessment of
exercise bout itself. In addition to a central mechanism function and the correlation of function with molecular
for maintaining blood flow to the working muscle and and cellular adaptations is not straightforward, reflect-
thus augmenting venous return, adaptation at the arte- ing the remarkable adaptability and compensatory na-
riolar level also occurs, as indicated by the increased ture of the cardiovascular system.
capacity for maximal vasodilation [i.e., a greater maxi- I)ADAPTATIONOFHEARTSIZE. Althoughitisgener-
mal conductance (271, 353, 362)]. All of these data indi- ally accepted that the increased functional demand
cate a training-induced enhancement of venous return placed on the heart by endurance exercise training will
by effectively increasing venous filling pressure. produce cardiac hypertrophy, exercise training models
II)INFLUENCEOFEXERCISEBRADYCARDIAONFILL- that produce changes in cardiac mass are not always as
ING TIME. One of the most striking effects of exercises consistent as would be expected when addressing the
training is the resulting bradycardia. The physiological mechanisms of the changes (160). In part, the difficulty
significance of the bradycardia on cardiovascular adap- arises from the desire to project what is observed in an
tations to exercise is apparent under the conditions of experimental animal to the human condition, which are
,&adrenergic receptor blockade. In untrained humans two entirely different hemodynamic situations. In addi-
given ,&adrenergic blockers while exercising at intensi- tion, there appears to be a strong genetic component to
ties requiring maximum oxygen consumption, cardiac cardiac function, as illustrated in dogs where, compar-
output is maintained at control levels (despite a slower ing racing greyhounds and mongrels, cardiac size does
heart rate) by increasing stroke volume (32). The slower not correlate well with cardiac functional parameters
heart rate allows a longer filling time and a greater (307). Furthermore, different types of exercise appear to
end-diastolic volume, resulting in a greater stroke vol- have different effects, i.e., endurance training in hu-
ume. The exact mechanism responsible for training bra- mans has a tendency to produce hypertrophy (normal-
dycardia remains elusive. Treadmill training of rats ized for lean body mass), whereas resistance training
produces a bradycardia that does not depend on ,& does not produce such a hypertrophy (relative to lean
adrenergic mechanisms, either systemically or cen- body mass) despite the apparently similar left ventricu-
trally, because receptor blockade with either the general lar contractility (80, 229, 254, 410). Therefore, adapta-
,&blocker propranolol or the cardioselective ,&blocker tion at the cellular and molecular level, despite its proba-
metoprolol does not prevent the training-induced brady- ble importance for functional adaptation, may not al-
cardia (296). This observation is consistent with the wavs be reflected functionallv.
570 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

One of the more popular models for inducing car- remembered that, with swim training, myocardial ,&
diac hypertrophy is that of increased myocardial wall adrenergic receptor density does not change (426), indi-
stress as a result of pressure overload (increased after- cating there is not the dogmatic up- or downregulation
load). As discussed below, this may not be an appro- of these receptors that might be expected from a recep-
priate model for studying exercise-induced cardiac hy- tor-mediated stimulation. A role for glucocorticoids is
pertrophy, but it serves as an example of some of the also suggested, because the binding capacity for gluco-
points to be considered in adaptation of cardiac protein corticoids was increased in the heart of female rats that
expression. Early in the onset of pressure overload there were swim trained and exhibited cardiac hypertrophy
is an increased formation of ribosomes (62) and in- (174). In these same rats there is a decrease in plasma
creased protein synthesis rate in a manner that is appar- corticosterone levels and no change in androgens. How-
ently mediated by a CAMP-protein kinase mechanism ever, there is an additive effect of treadmill exercise and
(419, 436). Mechanical stretching of S49 mouse lym- cortisol acetate treatment on cardiac hypertrophy in fe-
phoma cells directly stimulates adenylate cyclase (418). male rats (241). In these animals the cortisol treatment
Furthermore, the period of exposure need only be brief causes a decreased corticosteroid and androgen binding
to produce such changes (436). In young rats, pressure capacity in the myocardium that was not modulated by
overload causes an increased c-rnyc mRNA expression the exercise.
in both atria and the left ventricle (287). Although ex- Therefore, perhaps not surprisingly, the mecha-
pression of the cellular oncogenes is generally consid- nisms of cardiac protein expression that are influenced
ered to be indicative of a growth “program,” the lack of by exercise apparently involve complex events. We
expression of r-fos in response to the pressure-overload noted that several signal transduction mechanisms may
model reflects a lack of mitotic activity in the hyper- be active and that the sight of action of these signals
trophy process (287). The link between cellular mecha- may be at several control points, i.e., transcriptional,
nisms involved in pathological hypertrophy (pressure translational, and posttranslational.
overload) and normal growth comes from the observa- II)ADAPTATIONOFMYOFIBRILLARPROTEIN. Adapta-
tion that in the normal growth process of the pig heart tions in cardiac myofibrillar protein expression are
the left ventricle maintains a greater rate of ribosome functionally important, because the contractile machin-
formation than the low-pressure right ventricle (57). ery modulates calcium sensitivity and transduction of
This suggests, therefore, that at least some of the fea- chemical energy into mechanical work (13,24, 190,299,
tures of the control of protein expression in the pres- 395). As with cardiac hypertrophy, some of the adapta-
sure-overloaded heart are similar to those involved in tions observed are dependent on the exercise model em-
exercise-induced cardiac hypertrophy. ployed.
However, induction of pressure overload may not be From a pedagogic point of view, the shifts that oc-
the mechanism for exercise-induced cardiac hyper- cur in myosin isoform expression as a result of exercise
trophy, because the effect of swim training on myosin training in rats appear to be compensatory for the pro-
isoforms, ATPase activity, and functional indexes are gressively decreased pCa required for activation of the
the same in both normal and spontaneously hyperten- myofibrils (decreased contractility) during an acute
sive rats (354). Also, the head-down tilt caused in the bout of exhaustive exercise (27, 29), that is, toward a
rodent tail-traction model of hindlimb nonweight bear- more energetically active isoform. In swim-trained rats
ing, a posture that should produce a transient volume there is either a shift in the relative distribution of the
overload and increased hydrostatic afterload, causes a myosin isoforms toward the V, species (269,299,381) or
decrease in myocardial total mixed protein synthesis no change in the isoform profile (51). However, in both
rate within just a few hours (396). It is interesting that normotensive and hypertensive rats given swim train-
despite this decrease in protein synthesis rate, no car- ing in one study, despite the hypertrophy, no change was
diac atrophy occurs (indicating a concomitant decrease observed in isoform profile (all V,) or Ca2+-activated
in protein degradation) (399). Nonetheless, when tread- ATPase activity, but an increase in stroke and cardiac
mill-running exercise is given adjunct to the nonweight- performance indexes was noted (354). In another study,
bearing hindlimb, significant cardiac hypertrophy does a functional improvement of hypertensive rats with
occur (398). Therefore, although there may be specific swim training was also observed, although this time it
cellular and molecular changes as a result of increased was accompanied by a shift in the myosin isoform pro-
pressure, as a cellular system the adaptations may not’ file (344). Functional improvement with swim training
be expressed as a functional adaptation. has also been observed accompanied by a decreased ex-
A mechanism for exercise-induced cardiac hyper- pression of the V1 myosin isoform (51). These results are
trophy that is not mediated by wall stress must also be in contrast to those of Pagani and Solar0 (299) in whose
considered based on the following evidence. Isoproter- study swimming exercise caused an increase in the
onol is known to cause cardiac hypertrophy (383) with- Ca2+-stimulated ATPase in the trained animals, with no
out changing functional capacity (17). The fact that a change in M$+-stimulated ATPase, as well as a shift
receptor-mediated mechanism may be involved is sug- toward the V, myosin isoform. It is interesting to note
gested by the observation that in male rats, ,&adrener- that in the latter study, hypothyroid animals receiving
gic receptor blockade can prevent a treadmill training- the swim training did not exhibit the shift in myosin
induced cardiac hypertrophy (213). However, it must be isoform profile toward the V1 isoform. We must there-
April 1991 EXERCISE TRAINING ADAPTATIONS 571

fore conclude that the relationship between improved creased number of low-affinity sarcolemmal Ca2’-bind-
cardiac performance and changes in myosin isoform ing sites (402). Part of the increased Ca2+-binding
profile is at best tenuous and oversimplified. capacity may be a result of the increase in phosphati-
Treadmill-running exercise has a considerably less dylserine content of the sarcolemmal membrane (404),
striking effect on myosin isoform profile than does although the possibility of an effect of the altered lipid
swim training. As noted by Baldwin (14) and Baldwin et composition on the L-type Ca2+ channel has not been
al. (16), even in species with a large potential for myosin investigated. In support of this possible effect of altered
isoform shifts toward the V, isoform, there is little evi- lipid composition on the Ca2’ channel is the evidence
dence to suggest the occurrence of such a shift. Further- that an 11-wk training program of rats decreased the
more, the age-induced shift in myosin isoforms from V1 K, of the Na+-Ca2’ exchanger in sarcolemmal vesicles
to a more equal disposition of all three isoforms in the from 36.1 to 15.7 PM with no alteration of Vmax(403).
rat myocardium is not affected by treadmill training This electrogenic exchanger is sensitive to changes in
(100). Thus it appears as if the control of cardiac myosin plasmalemmal lipid composition (312). As noted, the
isoform expression during treadmill training is under a lipid profile of the sarcolemmal membrane from the
stringent control to prevent shifts in profile. Indeed this hearts of trained animals does change, and this could
control may be independent of contractile function, as account for the change in K, of the Na+-Ca2+ exchanger
indicated by the data on trained neonatal rats, where as well as possible alteration in the L-channels. Re-
the shifts in isoform expression during a 9-wk treadmill cently, ANP was shown to stimulate the L-type channel
training program are exaggerated in sympathectomized in bovine glomerulosa cells, leaving open the possibility
animals (283). Furthermore, the metabolic state of rats of an endocrine modulation of this channel as a conse-
also controls myosin isoform expression, as indicated by quence of exercise training (258). Furthermore, ANP
the shift in myosin isoform profile that can be induced can alter the selectivity of the cardiac sodium channel
by modifying dietary carbohydrate (282). However, an such that it can conduct Ca2’ (366). Another possible
infarct-induced shift in rat myosin isoform profile from effect of exercise training on the sarcolemmal Ca2’
the V, isoform to the V, and V, isoforms is partially channel is suggested from the observation that the level
reversed by treadmill training but does not result in any of the stimulatory guanine nucleotide binding protein
alteration in maximum cardiac output or stroke volume (G,) increases in the hearts of treadmill-trained pigs
(288). Covalent modification of the cardiac contractile (157); this protein has been shown to activate the Ca2’
proteins may also be an adaptation that enhances car- channels from bovine sarcolemma (202). Together, these
diac output. Phosphorylation of myosin light chains has factors could serve to increase Ca2+ flux across the sar-
been correlated with positive inotropic effects in rats colemma as an adaptation to exercise training.
(238). Furthermore, myosin light-chain phosphate con- Although it would not directly affect contractility,
tent correlates with the double product (heart rate X hyperkalemia would eventually compromise cardiac con-
pressure), a factor in minute work (109). The idea that traction (and a few other vital processes). Therefore it is
this mechanism may play an important role in the interesting to note that swim training of rats increases
trained individual is based on the observation that, in the K+-dependent 3-0-methylfluorescein phosphatase
treadmill-trained rats, there is an increased Ca2+-stimu- activity in the myocardium (indicative of ATPase activ-
lated myofibril ATPase and an increase in catechol- ity) as well as the number of [3H]ouabain-binding sites
amine-stimulated myosin light-chain phosphorylation in skeletal muscle (236). In humans, the level of expres-
(324), a response correlated with positive inotropic ef- sion of the Na+-K+-ATPase in myocardial biopsies corre-
fects (238; Fig. 4C). lates with ejection fraction measured in the same indi-
In general terms, the inotropic training adaptation vidual (235). These data provide evidence that both cen-
of the cardiac myofibrillar protein, if indeed one occurs, tral and systemic adaptations in the expression of
is toward an energetically more active condition. An ex- Na+-K+-ATPase in response to exercise training occur,
ample of this is evident in the shift in myosin isoforms possibly to minimize the potential for hyperkalemia.
toward the V, isoform. Furthermore, covalent modifica- B) Sarcoplasmic reticulum. As the primary store of
tion of these proteins appears to also be concerted to- intracellular Ca2+, the sarcoplasmic reticulum (SR) pro-
ward providing a more responsive system to inotropic vides an important, albeit difficult, organelle to study
stimulation. An example of this effect is enhanced phos- the regulation of cardiac contractility. Swim training in
phorylation of the phosphorylatable light chain of myo- rats produces an adaptation in the SR that provides a
sin in treadmill-trained rats without a difference in greater sequestering capacity (268, 309), perhaps pro-
CAMP levels compared with control animals (324) and viding a more rapid cycling of Ca2+ during the cardiac
changes in contractility associated with activation of cycle. This should facilitate relaxation, which would be
CAMP pathways are correlated with the proportion of important for coronary perfusion at a rapid heart rate.
the V, isoform (430). The exact mechanism for such an adaptation is not ap-
III) ADAPTATION OF THE PLASMA MEMBRANES. A) parent, however, because despite the increased SR Ca2+
Sarcolemma. Treadmill exercise training induces a binding and uptake there is no difference between
lengthened plateau phase of the cardiac action poten- swim-trained and control rats in SR Ca2’-ATPase activ-
tial, indicative of increased Ca2’ flux across the sarco- ity (268). This may be an age-dependent effect, however,
lemma1 membrane caused, at least in part, by an in- since senescent male rats show a marked improvement
572 FRANK W. BOOTH AND DONALD B. THOMASON Volume 71

in papillary muscle contractile function with treadmill sensitivity. However, in humans, isoproteronol-stimu-
training accompanied by an increase in the rate of Ca2’ lated CAMP production in lymphocytes was diminished
uptake by the SR (384). In contrast, no change is ob- with endurance training but not with resistance train-
served in the cardiac SR Ca2+ uptake of treadmill- ing, without an apparent change in sensitivity (214,215).
trained dogs who were not senescent (367). In addition, Nonetheless, in treadmill-trained pigs the decreased or
an increase in intracellular Ca2+ concentration will in- unchanged ,8-adrenergic receptor density presented an
crease Ca2’ release from the SR before the Ca2+-induced increased sensitivity of heart rate to isoproteronol(l57).
Ca2’ release phenomenon (99). Therefore the aforemen- This may be a result of increased levels of G, (157). In
tioned adaptations in the sarcolemmal membrane that this respect the treadmill training differs from pressure
enhance sarcolemmal Ca2+ flux would also produce an overload where there is an increased ,&adrenergic re-
effect at the SR. ceptor density and decreased adenylate cyclase activity
IV) ADAPTATIONS IN CATECHOLAMINE SENSITIVITY. and G, levels (253). There may also be an increased sensi-
The effect of circulating catecholamines on myocardial tivity of myosin light-chain kinase to CAMP stimulation
contractility is a well-documented phenomenon. There- as indicated by the increased rate and extent of catechol-
fore the decrease in resting plasma catecholamine levels amine-stimulated myosin light-chain phosphorylation
resulting from exercise training, with the more dra- in the hearts of treadmill-trained rats despite the lack
matic reductions occurring in endurance-trained ath- of a difference in CAMP levels between trained and con-
letes as opposed to resistance-trained athletes (214, trol hearts (324). However, this observation has not
428), may impact on myocardial contractile adaptations. been corroborated in treadmill-trained rats by the re-
These should be reflected at the receptor or postreceptor cent data of Fitzsimons et al. (110).
level. One problem with assessing adrenergic receptor On the whole, exercise training apparently pro-
changes is the inability to obtain tissue samples from duces an increased sensitivity to catecholamines in the
humans. However, an important observation is that the heart, either at the level of the receptor or by a postre-
variation in lymphocyte adrenergic receptors may be ceptor mechanism. However, regional differences in re-
indicative of variation in other tissues (1,42). ceptor-mediated catecholamine sensitivity also occur.
This observation has allowed exercise training ad- Therefore it is not too surprising that left ventricular
aptation of adrenergic receptors to be studied in hu- function and catecholamine levels are not strongly
mans using blood samples. correlated, making plasma catecholamine levels a poor
In humans, a decreased ,&adrenergic receptor den- indicator of inotropic effects in dogs (439) and inotropic
sity on lymphocytes in endurance-trained individuals and chronotropic effects in humans (379).
has been observed in one study, but this decrease in den-
sity is absent in resistance-trained athletes (214, 215).
This observation contrasts with the lack of change in B. Chronotropic Adaptations
lymphocyte ,&adrenergic receptor density previously
observed with running exercise training in humans seen As mentioned in section XA~II, exercise training-
by Williams et al. (424) and the increase observed by induced bradycardia has significant functional conse-
Lehmann et al. (252). However, lymphocyte receptors quences for the heart. The mechanism by which this
are not indicative of regional variation in receptor den- bradycardia develops is not clear, however. Exercise bra-
sity, as indicated by a decrease in the right atria1 ,& dycardia occurs only in endurance-trained subjects
adrenergic receptor density in treadmill-trained pigs (252) during ergometric tests, indicating an increased
but no change in left ventricular density (157). Of note is vagal tone in these subjects because decreased plasma
the lower cu-adrenergic receptor density on platelets of levels of catecholamine are observed in both resistance-
weight lifters and perhaps a greater receptor sensitivity trained and endurance-trained subjects. However, in
in endurance-trained athletes (214,215). This increased the context of chronotropic adaptation, adrenergic re-
sensitivity could be the mechanism by which the circu- ceptor sensitivity is not altered with training, as evi-
lating catecholamine levels are diminished as a result of denced by the lack of change in the responsiveness of
presynaptic feedback inhibition. However, resistance- heart rate to catecholamine infusion (422). Therefore
trained subjects apparently have a greater cY-adrenergic the decreased circulating levels of catecholamines may
receptor density on lymphocytes (252). nonetheless be important in modulating intrinsic heart
At the postreceptor level there appear to be exer- rate. Because the sympathetic and parasympathetic
cise-induced adaptations that augment the response to mechanisms for controlling heart rate are opposed, Ra-
catecholamines. In trained cats there is an increased ven and co-workers (360) have defined the concept of
responsiveness of adenylate cyclase to catecholamines “autonomic balance” for the relative influence of para-
(435). There is also an increased sensitivity to catechol- sympathetic and sympathetic tone. Trained subjects
amines of the papillary muscle of swim-trained rats as have an autonomic balance that is shifted toward
manifested in the isoproteronol-induced increased iso- greater parasympathetic influence (360).
metric tension and the change in tension per unit of Despite this conceptualization, the exact cellular
time relative to control tissue (381). In this study they mechanism for exercise bradycardia remains to be elu-
found that an increased affinity of the receptors, and cidated. Very probably there is a central nervous mecha-
not receptor number. was responsible for the increased nism for the autonomic balance. but cellular adapta-
April 1991 EXERCISE TRAINING
tions in the sinoatrial node may also occur. For example,
acetylcholine inhibits the hyperpolarization-activated
(pacemaker) current in the sinoatrial node cells at con-
centrations much lower than required to activate the
potassium channels previously thought to control pace-
maker activity in these cells (81). This means that only a
slight increase in vagal tone is required to slow heart
rate. In addition, the mechanism of acetylcholine action
is to inhibit adenylate cyclase activity (82, 3.29), poten-
tially altering pacemaker activity through a second mes-
senger action. However, such a process would be slow on
a beat-to-beat basis, and recent evidence has shown that
the pacemaker currents are readily modulated by direct
interaction of the G proteins with the channel (437).
Therefore, given the adaptations that can occur at the
receptor and postreceptor level, a large change in vagal
tone would not necessarily be required to produce exer-
cise bradycardia in trained subjects. The possibility of
cellular adaptation is supported by the data from
myocardial-infarcted rats in whom the diminished
maximum heart rate can be reversed by treadmill train-
ing (288).
XI. ADAPTATIONS THAT AFFECT CARDIAC AND
PERIPHERAL BLOOD FLOW
A. Coronary Blood Flow
The coronary vascular system adapts at the cellular
level to changes in functional demand that result from
exercise training. There is an increase in coronary ar-
tery size and capillary number with training (394) that
suggests an angiogenesis. In swim-trained rats a 15-
18% increase in coronary vascular reserve occurs more
rapidly than does hypertrophy (50), indicating a more
complex mechanism than simple growth; in treadmill-
trained miniature swine, coronary vascular reserve in-
creases 22% and the capillary exchange capacity (as de-
termined by the permeability-surface product) in-
creases 51% (247). As a result of the increase in
capillary density, there is a decreased diffusion distance
for oxygen to the working cells (52). An exception to the
increase in capillary density may occur in swim-trained
rats where a decreased capillary density has been ob-
served (113). However, in these animals capillary vol-
ume remains constant and is accounted for by an in-
creased capillary width (113), which manifests itself
functionally as an increase in coronary blood flow in
swim-trained rats (269). It is interesting to note that in
severely hypertensive rats there is a decreased capillary
density in the heart with endurance training despite an
improved functional capacity, which is in support of our
previous contention that a pressure-overload model is
not a model for exercise-induced cardiac hypertrophy
(270). This decreased capillary density may account for
the decreased coronary blood flow that is manifest in
hypertensive rats even after swim training (269).
ADAPTATIONS 573
B. Muscle Blood Flow
Although total hindlimb blood flow does not change
with treadmill training in rats, flow is greater to the
trained muscle and the visceral organs during exercise
(10, 332). This indicates an adaptation in the arterial
tone specific to the trained muscle as well as a reflex
adaptation.
Receptor-mediated control of muscle arterial tone
has some effect but cannot explain all of the exercising
muscle-specific adaptations that are observed. For ex-
ample, ,&adrenergic receptor blockade of rats running
at low speed decreases flow to all muscles, but at high
speeds ,&blockade has no effect (246). Also, muscarinic
receptor adaptations apparently do not play a role in the
shift of blood flow to muscle during either the preantici-
patory phase or during slow locomotor activity because
atropine does not alter the flow (11). Furthermore, the
decreased resting blood pressure observed in hyperten-
sive trained rats is not associated with decreased arte-
rial reactivity to norepinephrine (93). Nonetheless,
there is an increased sensitivity to infused catechol-
amines in vasodilator and systolic pressor responses in
humans, as indicated by decreased diastolic pressure
and increased systolic pressure (379). As a consequence
of these mixed responses, other factors must be consid-
ered that may be involved in the decrease arterial tone.
Hyperpolarization of arterial smooth muscle can cause
vasodilation, and several hormones may act by a mecha-
nism that directly (vasoactive intestinal peptide) or indi-
rectly (acetylcholine through endothelium-mediated
factor release) activates an ATP-sensitive potassium
channel, causing hyperpolarization (370). Exercise adap-
tation in the arterial smooth muscle may alter the sensi-
tivity or action of these channels. Such an increased sen-
sitivity to external vasodilators may be the reason for
decreased peripheral resistance in trained subjects dur-
ing recovery from exercise (76).
Reflex vasoconstriction may play a role in main-
taining flow to exercising muscle as well as the in-
creased visceral flow observed as a result of exercise
training. In barodenervated rabbits there is a lack of
diversion of blood flow toward exercising muscle that is
manifest as a large decrease in mean arterial pressure
at the onset of exercise, a decrease in maximum coro-
nary flow at rest and exercise, and no change in kidney
blood flow or muscle blood flow (156). A desensitization
of this baroreflex with training would contribute to the
maintenance of flow to the visceral organs (26) as well
as contribute to the attenuation of the response of renal
sympathetic nervous activity, which may play a role in
training-induced hypervolemia (78).
Blood flow to exercise-trained muscle is also aug-
mented by an increased capacity for flow (248,264,353),
which may, at least in part, be a result of an increased
capillarity (266). The increased capacity for flow is de-
pendent on the training intensity, as apparently are in-
creases in the capillary filtration (either intrinsic or due
to increased capillarity) (248,353). Significantly, the in-
crease in total vascular conductance that results from
574 FRANK W. BOOTH AND DONALD B. THOMASON VolunLe 71

training is a result of decreases of the same magnitude
in both pre- and postcapillary resistance (353), an adap-
tation that not only augments flow (Fig. 4B) but also
does not alter the balance of fluid movement between
capillary and interstitium.
trained heart would contribute to the smaller increases
in plasma lactate and smaller decreases in plasma pH
during exercise (180), providing a means for extending
the length of exercise time at maximal levels.

B. Oxidative Phosphorylation
XII. ADAPTATIONS THAT AFFECT CARDIAC MYOCYTE
METABOLISM As determined by 31P-nuclear magnetic resonance,
an increase in myocardial oxygen consumption may oc-
Despite the fact that endurance-trained individuals cur with only small changes in phosphate metabolites
exhibit a decreased heart rate-pressure product and but may be stimulated instead by Ca2+, a phenomenon
thus have a decreased minute work (76), adaptations termed “stimulus-response-metabolism coupling” (273).
occur in cardiac muscle metabolism to apparently make By the same mechanism as the contractility adaptations
the work more efficient and better sustained. that occur because of enhanced Ca2+ availability, oxida-
tive phosphorylation in trained cardiac muscle may be
stimulated. However, in treadmill-trained rats, cardiac
A. Substrate Metabolism mitochondria exhibit a decreased retention of Ca2+ and
fewer transport sites (367). Despite the apparent lack of
One of the more striking responses of the myocar- an increase in mitochondrial protein in the hearts of
dial biochemistry to exercise is the twofold increase in treadmill-trained rats (213) and the lack of an increase
CAMP levels in the myocardium for 24 h after exercise, in myocardial mitochondrial density (136,297), ubiquin-
despite an increased phosphodiesterase level (306). This one and cytochrome c are increased in concentration
response to an acute bout of exercise is the same for with endurance training (33).
trained and nontrained rats (304,305). ,&Adrenergic re- However, different training protocols may have
ceptor blockade or adrenalectomy inhibits the increase differential effects, as suggested by the increased mito-
in CAMP concentration (302). Another adrenergic re- chondrial-to-myofibril volume density in swim-trained
ceptor-dependent event appears to be the treadmill rats (113). A reversal of the decreased mitochondrial-to-
training-induced increase in myocardial hexokinase ac- myofibril volume ratio in hypertensive rat myocardium
tivity, which is blocked by ,&adrenergic antagonists is observed after treadmill training, perhaps by the
(213). The large increase and maintenance of CAMP lev- same mechanism (72). The senescence-associated de-
els in the myocardium is interesting when it is consid- crease in cytochrome c concentration in the heart was
ered that, for catechol-induced lipolysis, the activation reversed by a 4-rnoj program of treadmill running
of triacylglycerol lipase by CAMP appears to be me- started at age 21 mo in rats (371). Interestingly, &ami-
diated by protein kinase C (303). Therefore the adapta- nolevulinic acid synthase activity increases with an
tion in the responsiveness of adenylate cyclase discussed acute bout of exercise in the untrained animal but not in
would be manifest as an increase in lipolysis, providing the trained animal (2). These data indicate that what-
a more efficient utilization of energy. ever stimulatory effect exercise training has on mito-
In addition to these lipolytic adaptations, there is chondrial expression occurs rapidly and then returns to
an increase in glycogen content in swim-trained rats at a steady state as training progresses.
rest (347), cardiac glucose uptake is enhanced in swim-
trained rats, and there is a dissipation of the endocar-
dium-epicardium glucose uptake gradient in swim- and XIII. CONCLUSION
run-trained rats (217,218). These adaptations occur in-
dependently of the actual cardiac work load or the avail- We outlined many of the molecular and cellular ad-
ability of other substrates and thus are apparently a aptations that occur in skeletal muscle and the cardio-
result of an enhancement at the level of the glucose vascular system as a result of exercise training. In addi-
transporter (218). It is interesting to note that, in skele- tion, some of the molecular and cellular adaptations oc-
tal muscle, the contraction-induced translocation of curring in response to models of increased contractile
protein kinase C precedes an enhanced glucose uptake activity that do not mimic human sports are given. An
(64); perhaps a similar mechanism for enhanced glucose underlying theme is the concept that adaptability
transport in cardiac muscle occurs as a result of the serves to provide less disruption of the milieu interieur,
increased CAMP levels observed by Palmer and co- minimize fatigue, enhance performance, and improve
workers (303-305). the economy of energy expenditure during exercise.
Swim training of rats increases the M, isoform of From the point of view of classic evolutionary theory,
lactate dehydrogenase in the myocardium from 28 to the genetic trait of adaptability is maintained.
33% (438), consistent with the decreased Km of lactate With aerobic training there is a shift in the trained
dehydrogenase for lactate observed in the hearts of run- skeletal muscle to greater reliance on oxidative metabo-
ning exercise-trained rats (212). Consequently, the po- lism to provide energy, although at a diminished oxygen
tential for the greater utilization of lactate by the flux per mitochondrion. Furthermore, the contractile
April 1991 EXERCISE TRAINING ADAPTATIONS 575

machinery of the trained muscle adapts to utilize energy changes in the subgroups of human type II skeletal muscle fibres.
more efficiently. With resistance training, the primary Acta Physiol. Stand. 99: 123-125, 1977.
adaptation is the distribution of the load across a 8. APPLE, F. S., AND M. A. RODGERS. Skeletal muscle lactate
dehydrogenase isozyme alterations in men and women marathon
greater muscle mass. runners. J. AppZ. PhysioZ. 61: 447-481, 1986.
The cardiovascular system adapts to exercise train- 9. APPLE, F. S., AND P. A. TESCH. CK and LD isozymes in human
ing by minimizing the energy cost of the work. To pro- single muscle fibers in trained athletes. J. AppZ. PhysioZ. 66: 2717-
vide the necessary work, increases in pressure work and 2720,1989.
10. ARMSTRONG, R. B., AND M. H. LAUGHLIN. Exercise blood
heart rate are minimized in favor of augmented stroke flow patterns within and among rat muscles after training. Am.
volume. To this end adaptations in both inotropic func- J. PhysioZ. 246 (Heart Circ. Physiol. 15): H59-H68, 1984.
tion and blood flow occur. Furthermore, cardiac myo- 11. ARMSTRONG, R. B., AND M. H. LAUGHLIN. Atropine: no effect
cyte metabolism adapts to the demands of training to on exercise hyperemia in conscious rats. J. AppZ. Physiol. 61: 679-
provide a more efficient and better sustained energy 682,1986.
12.ARMSTRONG, R. B., P. MARUM, P. TULLSON, AND C. W. SAU-
SUPPlY l
BERT IV. Acute hypertrophic response of skeletal muscle to re-
Physiologists have just begun to describe and inte- moval of synergists. J. AppZ. Physiol. 46: 835-842, 1979.
grate the many factors that comprise the “exercise- 13. BABU, A., E. SONNENBLICK, AND J. GULATI. Molecular basis
training response.” These adaptations function to pro- for the influence of muscle length on myocardial performance.
Science Wash. DC 240: 74-76, 1988.
vide a less taxing, and more enjoyable, response to the 14. BALDWIN, K. M. Effects of chronic exercise on biochemical and
physical demands of exercise. Furthermore, to define functional properties of the heart. Med. Sci. Sports Exercise 17:
the mechanisms underlying these adaptations to physi- 522-528,1985.
cal activity requires the synthesis of knowledge from 15. BALDWIN, K. M., W. G. CHEADLE, 0. M. MARTINEZ, AND
D. A. COOKE. Effect of functional overload on enzyme levels in
multiple disciplines (systems physiology, adaptive phys- different types of skeletal muscle. J. AppZ. PhysioZ. 42: 312-317,
iology, biochemistry, cell biology, molecular biology, in- 1977.
tegrative physiology, biophysics) to explain how the un- 16. BALDWIN, K. M., D. A. COOKE, AND W. G. CHEADLE. Time
anesthetized human can survive high levels of physical course adaptations in cardiac and skeletal muscle to different
stress. running programs. J. AppZ. Physiol. 42: 267-272, 1977.
17. BALDWIN, K. M., S. B. ERNST, W. J. MULLIN, L. F.
We gratefully thank Lawana Norris for the care with SCHRADER, AND R. E. HERRICK. Exercise capacity and car-
which the manuscript was prepared. We also appreciate the diac function of rats with drug-induced cardiac enlargement. J.
AppZ. PhysioZ. 52: 591-595, 1982.
many helpful comments and suggestions given by Drs. G. Ste-
18. BALDWIN, K. M., R. H. FITTS, F. W. BOOTH, W. W. WINDER,
phen Morris, George Taffet, Charlotte Tate, Adrian Sheldon, AND J. 0. HOLLOSZY. Depletion of muscle and liver glycogen
and the unknown reviewers. We also thank Drs. Phil Gollnick, during exercise. Protective effect of training. PJEuegers Arch.
John Holloszy, and Charles Tipton, whose teaching and re- 354: 203-212,1975.
search fostered the field of exercise biochemistry. 19. BALDWIN, K. M., V. VALDEZ, R. E. HERRICK, A. M. MACIN-
This work was supported by National Institutes of TOSH, AND R. R. ROY. Biochemical properties of overloaded
Health Grant AR-19393 (to F. W. Booth) and National Aero- fast-twitch skeletal muscle. J. AppZ. Physioh 52: 467-472, 1982.
nautics and Space Administration Grant NAGW’i’O (to D. B. 20. BALDWIN, K. M., W. W. WINDER, AND J. 0. HOLLOSZY. Adap-
‘l’homason). tation of actomyosin ATPase in different types of muscle to en-
durance exercise. Am. J. Physiol. 229: 422-426,1975.
Present address of D. B. Thomason: Dept. of Physiology, 21. BALDWIN, K. M., W. W. WINDER, R. L. TERJUNG, AND J. 0.
Univ. of Tennessee Medical School, Memphis, TN 38163. HOLLOSZY. Glycolytic enzymes in different types of skeletal
muscle: adaptation to exercise. Am. J. Physiol. 225: 962-966,1973.
22. BAR, A., J.-A. SIMONEAU, AND D. PETTE. Altered expression
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