Lactoat y Resapiracion Mitocondrial

Acta Physiol Scand 2000, 168, 643656
Lactate as a fuel for mitochondrial respiration

G. VAN HALL
The Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark
ABSTRACT
Lactate production in skeletal muscle has now been studied for nearly two centuries and still its
production and functional role at rest and during muscle contraction is a subject of debate.
Historically, skeletal muscle was seen mainly as the site of lactate production during contraction and
lactate production associated with a lack of muscle oxygenation and fatigue. Later, it was recognized
that skeletal muscle not only plays an important role in lactate production but also in lactate clearance
and this in turn has led to a renewed interest in the metabolic fate of lactate in skeletal muscle and
also in other tissues. Studies using lactate isotopes have shown that skeletal muscle extracts lactate
from the circulation despite a substantial net lactate release, and that skeletal muscle has a large
capacity for lactate oxidation; these processes being enhanced with exercise. Lactate dehydrogenase
(LDH) controls the formation of lactate and may regulate the turnover of lactate in the muscle cell.
Skeletal muscle contains five LDH isoforms (LDH15). Of the ve LDH isoforms, the heart-specic
LDH1,2 is generally suggested to favour the reaction of lactate to pyruvate whereas the musclespecic LDH4,5 isoform favours lactate formation. However, in this paper, it is argued that
compartmentalization of the muscle cell and LDH association with cell structures may play a more
predominant role in whether the LDH reaction proceeds towards lactate or pyruvate formation. The
model for skeletal muscle lactate metabolism presented is in essence based on a synthesis of old
and more recent studies on skeletal muscle lactate transport, uptake, release, oxidation, and the role
of LDH at rest and during exercise.
Keywords exercise, isotopes, lactate dehydrogenase, lactate shuttle, oxidation, pyruvate, skeletal
muscle.
Received 28 November 1999, accepted 9 December 1999
Lactate production in skeletal muscle has now been

studied for nearly two centuries and still its production
and functional role at rest and during exercise is a
subject of debate (see for historical overview Karlsson
1971). Despite a wealth of studies showing that lactate
can be taken up by skeletal muscle and oxidized, lactate
is still considered by many as a metabolic end product.
The supplementary anaerobic energy provided by
glycolysis also gives rise to increased lactate formation
along with other metabolites linked to muscle fatigue,
and hepatic removal of lactate is the primary means for
recycling lactate via gluconeogenesis. However, already
in 1907 Fletcher & Hopkins not only provided denitive evidence of the relation between muscle activity
and production of lactic acid in the amphibian muscle
but they also concluded that `the muscle in itself
possesses the requisite chemical mechanism for the
removal of lactic acid once formed, and that it is not in
this respect wholly dependent upon the circulation,
indicates that lactic acid is a product of its normal

metabolism' (Fletcher & Hopkins 1907).
In the twenties and thirties, it was observed that
blood lactate concentration fell more rapidly in
recovery when moderate intensity exercise was
performed instead of a passive recovery (Jervell 1928,
Newman et al. 1937). Later, it was shown that during
exercise, lactate was taken up by muscles not participating in the exercise (Carlson & Pernow 1959, Freyschuss & Strandell 1967, Ahlborg et al. 1975). When the
arterial lactate concentration was elevated, the exercising muscle was also able to take up lactate (Stainsby
& Welch 1966, Freyschuss & Strandell 1967, Richter
et al. 1988) and when cycle ergometer exercise was
performed with one leg with a normal glycogen
concentration and the other leg with a low glycogen
concentration, the leg with a normal glycogen content
was releasing lactate whereas the leg with the low
glycogen content was taking up lactate (Essen et al.
Correspondence: G. Van Hall, The Copenhagen Muscle Research Centre, Rigshospitalet section 7652, 20 Tagensvej, DK-2200 Copenhagen N,
Denmark.
2000 Scandinavian Physiological Society
643
Lactate as a fuel for mitochondria
G Van Hall
1975, Gollnick et al. 1981). The uptake of lactate by

skeletal muscle appeared to be higher when light
exercise was performed compared to rest (Rammal &
Strom 1949, Richter et al. 1988). From these studies, it
became clear that skeletal muscle not only plays an
important role in lactate production but also in lactate
removal from the circulation. The ability of skeletal
muscle for lactate utilization, uptake and potentially
mutual release was further studied with lactate isotopes.
Animal experiments in the fties showed that lactate
was taken up and partially oxidized in skeletal muscle
(Drury & Wick 1956) and that lactate oxidation was
higher in exercising compared to resting muscle
(Omachi & Lifson 1956). Jorfeldt (1970) conrmed
these ndings in humans. Clearly, lactate is not an end
product of skeletal muscle carbohydrate metabolism
but instead seems to be an important fuel for mitochondrial respiration in skeletal muscle. This article will
review the existing literature regarding skeletal muscle
lactate metabolism, in particular the processes of lactate
transport, uptake, and oxidation and the role of lactate
dehydrogenase (LDH) isozymes in these processes will
be discussed.
L I M B L A CT A TE E X CH A N G E
AND OXIDATION
Most studies investigating muscle lactate metabolism
have measured lactate exchange across a limb from the
lactate concentration difference of an artery and the
vein draining the muscle bed. Generally, a small net
lactate release from the limb was observed at rest and
this release increased with exercise. However, with the
use of 14C-lactate isotopes, it was shown that there was
actually a mutual uptake and release of lactate (Jorfeldt
1970, Stanley et al. 1986, Consoli et al. 1990). The
studies of Jorfeldt (1970) are illustrative for muscle
lactate metabolism during prolonged moderate intensity
exercise, and the study of Stanley et al. (1986) shows the
effect of exercise intensity on muscle lactate metabolism. Therefore, these two studies, presented in
Fig. 1(a,b), will be discussed here in detail. Some limitation in their designs will be discussed in the `Methodological Considerations' section.
During prolonged exercise at moderate intensity, a
net lactate release from muscle is observed. As exercise
proceeds, the net lactate release decreases (Fig. 1a,
Jorfeldt & Wahren 1970) and may eventually decrease
to a level of no measurable release, depending on the
duration and intensity of the exercise. However, despite
the net lactate release during exercise, there is a lactate
uptake and the rate of uptake seems to remain constant.
Thus, during a prolonged bout of moderate intensity
exercise, the rate of muscle lactate uptake is constant
whereas the muscle net lactate release decreases
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Figure 1 Human lactate exchange across a limb. (a) Forearm lactate
net release, uptake and fractional oxidation during 47 min of exercise,

redrawn from Jorfeldt (1970). The net lactate release is calculated
from the arterialvenous difference of the lactate concentration
multiplied with the blood ow. The lactate uptake is calculated from
the fractional extraction of lactate multiplied with the arterial lactate
concentration and muscle blood ow. The fractional extraction of
lactate is calculated from the arterialvenous difference of labelled
lactate as a fraction of the arterial concentration of labelled lactate.
Fractional oxidation of 14C-lactate is calculated as the venousarterial
difference of 14CO2 as the fraction of the arterialvenous difference
of 14C-lactate. (B). Arm and leg net lactate exchange and leg lactate
uptake at rest and during cycle exercise, redrawn from Stanley et al.
(1986). A negative value for arm net lactate release signies a net
lactate uptake. Calculation are as above, except that no blood ow
was measured therefore rates are relative in mmol L1.
substantially with exercise duration. This seems to be

the same in conditions of enhanced blood lactate
concentration via lactate infusion, although the absolute
rate of net lactate release may be lower and lactate
uptake higher. In Fig. 1(b) the study of Stanley et al.
(1986) is presented. The absolute rate of lactate
exchange cannot be established, as the blood ow was
not determined. However, as all values increase with
increasing exercise intensity, this only means that the
absolute differences become larger when multiplied
with the blood ow, which has been shown to increase
linearly with workload. At rest, a small net lactate
release by arm and leg can be observed. Cycle exercise
at the low intensity of 49 W causes an increase in the

net lactate release as well as the lactate uptake by the
active leg. In contrast, the inactive arm switches to a net
lactate uptake. With increasing exercise intensity the net
lactate release increases as does the lactate uptake by
the active leg. Thus, the uptake of lactate by the muscle
increases with exercise compared with rest and
increases with increasing exercise intensity. This seems
to suggest that the metabolic rate is a main regulator of
muscle lactate uptake and metabolism, i.e. oxidation.
However, the arterial lactate supply also seems to affect
muscle lactate uptake for a given workload, i.e. metabolic rate, a 3-fold increase in arterial lactate concentration elicited a 2-fold increase in leg lactate uptake and
a corresponding increase in oxidation (Fig. 1a).
However, it cannot be excluded that the lactate infusion
may have caused a shift in muscle substrate utilization
via hormonal changes which may have elicited an
increased lactate and reduced fatty acids utilization.
Alternatively, the lactate infusion may have inhibited
muscle glycogenolysis and glycolysis at the expense of
an increased lactate usage as the respiratory quotient
was the same for the control and lactate infusion trial
(Jorfeldt 1970). Watt et al. (1994) investigated the effect
of metabolic rate on lactate uptake in the perfused
hindlimb of the rat. Mild electrical stimulation of the
hindlimb at a constant lactate concentration of 1 mM
doubled the hindlimb oxygen uptake and increased the
net lactate release 10-fold. However, the tracer-determined lactate uptake by the hindlimb was unchanged
and they concluded that the activity of the muscle itself,
e.g. metabolism, has no major effect on lactate transport into the muscle but predominantly on lactate
release. Most probably the lactate supply to the muscle
and changes in muscle metabolic rate are both a driving
force in lactate uptake. The latter has to play a role as
with exercise, lactate uptake and subsequent oxidation
can increase 10-fold or more, depending on exercise
intensity, and in order to utilize the lactate metabolic
rate has to be increased. Denitely more research is
needed to clarify the role of muscle metabolic rate and
lactate supply in muscle lactate uptake.
The major fate of the lactate taken up by skeletal
muscle seems to be oxidation. Omachi & Lifson (1956)
showed, in the isolated perfused dog gastrocnemius,
that lactate was oxidized and oxidation rates doubled
during contraction. The oxidation rates were 1213%
of [D,L-13C]lactate taken up in the unstimulated and
2529% in the stimulated muscles. Knowing that, the
`unnatural' D-lactate form is metabolized to a far lesser
extent than L-lactate in the body and potentially some
13
CO2 is retained in the muscle bicarbonate stores (Van
Hall 1999). Therefore, these values may be a 2-fold
underestimate and, thus presumably about 25%, and at
least 5060% of the lactate was oxidized in unstimu 2000 Scandinavian Physiological Society
G Van Hall
lated and stimulated skeletal muscles, respectively.

Jorfeldt (1970) showed that during exercise 50% of the
[U-14C]lactate taken up could be recovered as labelled
CO2, independently from the lactate uptake (Fig. 1a).
The duration of [U-14C]lactate infusion was only
10 min and steady-state in the extra- and intracellular
lactate and bicarbonate pools might not have been
reached despite an apparent steady-state. This may have
resulted in an overestimation of lactate uptake and
underestimation of 14CO2 production and thus in a too
low fractional lactate oxidation (Stanley et al. 1986).
More recently 70% of the [1-13C]lactate extracted by
the hindlimb of anaesthetized dogs was released as
labelled CO2 (Chinkes et al. 1994). Across the human
leg, 20% of the [1-13C]lactate extracted was recovered
1 as labelled CO2 at rest (Van Hall et al. 1999b). The
anaesthesia and fasting condition of the dogs might
explain in part the 3-fold higher oxidation of the lactate
taken up in the dog hindlimb compared with the
human leg. With moderate intensity exercise at 42%
VO2max, 90% of the lactate taken up by the leg could
be recovered as labelled CO2 (Van Hall et al. 1999b).
Summarizing the above-mentioned studies it seems that
at rest and, to a minor extent, during exercise some
lactate that is taken up by muscle is not oxidized and
therefore has to be metabolized into other metabolites.
Lactate may be incorporated in glycogen and alanine,
although the amount of lactate used for glycogen and
alanine synthesis in muscle has been suggested to be
small and together they may contribute 10%
(McDermott & Bonen 1992). An exception might be
under conditions of high muscle lactate concentration
as has been suggested during active recovery from a
short bout of high intensity cycling leading to high
intracellular lactate concentration. The inactive type II
bres used lactate for glycogen resynthesis and the
active type I bres oxidized lactate in preference to
glycogen (Nordheim & Vllenstad 1990). Another
possible reason for the low lactate uptake oxidized is
that the lactate uptake at rest is overestimated and the
appearance of labelled CO2 underestimated, potentially
caused by non-steady-state in the enrichment of the
extra- and intracellular lactate and bicarbonate pools.
The studies mentioned above have investigated
muscle lactate metabolism across a limb in humans or
other species and assumed that the majority of tissue
was represented by skeletal muscle. Moreover, in some
of those studies muscle lactate concentration was
measured in muscle biopsies which were assumed to be
representative for all limb muscles (for review see Van
Hall et al. 1999b). In Fig. 2(a), a schematic representation of a limb is given, for simplicity a schematic upper
leg is taken as representative of the whole limb. The leg
consists of several different muscles, all with specic
2 characteristics and bre types (Gollnick et al. 1974a, b).
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G Van Hall
Moreover, during exercise not all muscles of the leg will

be engaged to the same extent depending on the type,
duration and intensity of the exercise employed. This
646
has been shown using surface electromyography

(EMG) and T2-weighted magnetic resonance images
(MRI) (Green & Patla 1992, Richardson et al. 1998).
Figure 2 Schematic representation of leg lactate handling. (a) Sche-
matic upper leg. Lactate enrichment and concentrations are measured in

the femoral artery and vein. However, not all muscles in the leg
(upper leg) are engaged to the same extent in exercise. Furthermore,
exchange of lactate most likely cannot occur between bre bundles.
The thickness of the arrows indicates the relative quantity of the total
leg blood ow going to the different muscles. (b) Schematic muscle
bundle. Lactate exchange may occur within in a muscle bundle.
However, in humans bre type heterogeneity is present. The type I
bres are represented by darker red colour and type II bres by the
light red. (c) Schematic skeletal muscle cell. The thickness of the arrows
indicates the potential relative quantity of the lactate ow going to and
from the microcirculation and within the muscle cell during low to
moderate intensity exercise. Numbers are theoretical lactate ux rates
in mmol min1. The pink arrows represent lactate from the arterial
microcirculation and the green arrows represent the intracellular
produced lactate. The broken black arrow in the mitochondria
represents the proposed lactate transport into the mitochondria
49;50 (Szczesna-Kaczmarek 1990a, b, 1992, Brooks et al. 1999). MCT,
monocarboxylate transport system; GLUT, glucose transporter,
Green tetramer, lactate dehydrogenase bound to the myobrile and/
or associated to or within the sarcoplasmatic reticulum; Pink tetramer, lactate dehydrogenase associated with the mitochondrial
membrane or potentially in the mitochondrial matrix; [lactate], lactate
concentration; Lactate*, the 13C labelled lactate; *CO2, 13C labelled
CO2, originating from the metabolized 13C labelled lactate.
Therefore, studies on lactate metabolism across a limb

have measured an average of all muscles and bre
types. Theoretically, quiescent or mildly recruited
muscles during exercise may be a net consumer of
lactate, e.g. oxidize, whereas more active muscles may
be net producers. In fact, some degree of muscle
activity may enhance the ability to consume/oxidize
lactate as energy demand is higher. It is highly unlikely
that lactate can transfer from one muscle to another or
from one to another muscle bundle, thus the lactate has
to enter the main circulation before it can be re-utilized
(Fig. 2a). Within a muscle bundle, lactate can potentially
be produced in one bre and consumed in the other
when these are in relative close proximity to each other.
Already in 1930, Owles suggested that `lactate may be
produced in some muscles and subsequently oxidized
in others, or even adjacent bres of the same muscle'
(Owles 1930). So far, the main focus has been on type
II bres producing lactate and type I bres consuming
lactate. However, both type I and II bres have the
same enzymatic machinery and transport systems
available to handle lactate, although in different activities and quantities. Therefore, it seems unlikely that
lactate is exclusively produced in type II bres and in
part consumed in type I bres or that lactate taken up
from the circulation is exclusively consumed by the
type I bres. However, the described phenomenon of
one bre producing and another potentially consuming
the produced lactate may occur if during exercise not all
bres are recruited. To determine bre type recruitment
during cycle exercise, the single-bre glycogen deple 2000 Scandinavian Physiological Society
G Van Hall
tion technique has been used. From those studies the

general picture emerging is that at low exercise intensities (<40 VO2max) a portion of almost solely type I
bres are activated, whereas with increasing intensities
progressively more type I are recruited accompanied by
recruitment of type II bres (Gollnick et al. 1974a, b,
Vllestad 1985). Thus, during exercise there could be a
more important role for active vs. inactive muscles, and
active vs. inactive bres when considering the case of
one producing and another consuming lactate in a limb.
In addition, it has been suggested that active bres once
they become nearly depleted of glycogen take up lactate
as a carbohydrate source regardless of the bre type
(Essen et al. 1975). Nevertheless, LDH activity and
isozyme patterns are different in type I and II bres and
this may affect lactate metabolism at rest and during
exercise when both bre types are recruited. Pagliasotti
3 & Donovan (1990a, b, c) studied lactate turnover by
perfusing three different skeletal muscle preparations of
anaesthetized rabbits, glycolytic gracilis, oxidative
soleus, and a mixed preparation of gastrocnemius,
plantaris and soleus together (25% type I, 31% type
IIA, and 44% type IIB). Oxidative muscle preparation
started to show a net lactate uptake at a lactate
concentration of 2.5 mM, whereas the glycolytic and
mixed preparations showed a net lactate uptake at
4 mM. Furthermore, they also showed that the fate of
the lactate taken up was dependent on the bre type. At
8 mM of lactate, the apparent oxidation could account
for 51, 39, and 28% of total lactate removal by the
oxidative, mixed and glycolytic preparations, respectively. Lactate incorporation into glycogen on the other
hand accounted for 2, 26, and 48% of the total net
lactate removal by the oxidative, mixed and glycolytic
preparations, respectively. These studies suggest that
both, the rate and the route of lactate disposal are
affected by bre type composition of the muscle.
M E T H O D O L O G IC A L C O N S I D E R A T I O N S
The studies of Jorfeldt (1970) and Stanley (1986)
presented above have some limitation in their design
which may have inuenced the quantitative measurements. A prerequisite of arterialvenous difference
measurement across a tissue is a metabolic steady-state,
i.e. the Fick principle. In the studies of Jorfeldt (1970),
lactate metabolism during prolonged moderate intensity
exercise most likely was in a reasonable steady-state.
However, the [U-14C]lactate isotope was infused for
less than 10 min. It seems unlikely that an isotopic
equilibrium was reached in the muscle lactate pool in
that short period of infusion. This may have resulted in
an overestimation of the lactate uptake. Furthermore,
the 14CO2, produced from lactate being oxidized, can
hardly have reached an isotopic equilibrium with the
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intramuscular bicarbonate pools (Van Hall 1999),

despite an apparent plateau in 14CO2 release from the
forearm in the last few minutes of infusion. In addition,
some of the 14C-label of lactate may have been xed via
isotopic exchange reactions in the TCA-cycle and
consequently not appeared as 14CO2 (Sidossis et al.
1995, Van Hall 1999). The carbon in position 1 of
lactate is oxidized in the pyruvate dehydrogenase
reaction whereas the carbon label in the 2 and 3 of
lactate enter the TCA-cycle before being liberated as
CO2. However, in the latter case, carbon label might be
xed via isotopic exchange reactions in the TCA-cycle
and thus not appear as labelled CO2 depending on
changes in metabolic rate (Sidossis et al. 1995, Van Hall
1999). However, in general no substantial differences
have been observed between lactate labelled at different
carbon positions or uniformly labelled lactate (Pagliassotti & Donavan 1990a, b, c, Zhang et al. 1993, Chinkes
et al. 1994). Therefore, the observed lactate fractional
oxidation rate of 50% may have been a considerable
underestimation owing to an underestimation of 14CO2
production and an overestimation of lactate uptake.
The study of Stanley et al. (1986) suffers from a lack of
metabolic and isotopic steady-state as the exercise
intensity was changed each 6 min. As the blood ow
also was not measured, no quantitative data is present
dealing with the effect of exercise intensity on lactate
turnover in humans.
The use of the lactate isotope dilution methodology
to quantify muscle lactate consumption (isotopic
uptake) and production (isotopic release) has been a
subject of debate for many years. A prerequisite to
calculate metabolic consumption and production of
lactate across a tissue is that there is no isotopic
exchange between lactate and other compounds but
only metabolic incorporation via the involvement of
irreversible reactions (Wolfe 1992, Landau & Wahren
4 1992, 1993). However, the lactate isotope is actually
diluted by exchange through the pyruvate pool due to
the rapid isotopic equilibrium between lactate and
pyruvate. The argument is that labelled lactate entering
from the arterial circulation in the tissue pool is
converted to labelled pyruvate, and unlabelled pyruvate
is converted to unlabelled lactate, i.e. an exchange. A
rapid equilibration of lactate to pyruvate in blood has
been observed when labelled lactate isotope was
infused and the enrichment of lactate and pyruvate
were nearly identical (Wolfe et al. 1988, Romijn et al.
1994). These data seemed to indicate that lactate and
pyruvate are to be considered as one pool. However,
recent studies investigating lactate and pyruvate
exchange across the hindlimb and gut of anaesthetized
dogs (Chinkes et al. 1994) and the hindlimb of the rat
(Large et al. 1995) show that the muscle intracellular
enrichment of pyruvate is considerably lower than
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lactate. Preliminary data in humans showed that with

[1-13C]lactate infusion muscle pyruvate enrichment was
1323% of the muscle lactate enrichment at rest and
4649% during cycle exercise at 42% VO2max (Van Hall
et al. 1999a, b). However, some caution is warranted in
regard to the intracellular enrichment data as it cannot
be excluded that to some extent low muscle lactate and
pyruvate enrichment may originate from handling of the
muscle samples (Large et al. 1995). Dilution of the
enrichment may occur from dilution of the enrichments
by unlabelled lactate and pyruvate produced by ongoing
glycolysis during the time needed to obtain the muscle
sample and while processing the samples. On the other
hand, too high muscle enrichments of lactate and
pyruvate may also be obtained due to contamination of
the muscle tissue by blood. If the muscle biopsies are
not freeze dried and freed completely, the high blood
enrichment of both pyruvate and lactate results in excess
intracellular muscle enrichments. However, it seems that
muscle pyruvate enrichment is lower than muscle lactate
enrichment. This might imply that the muscle pyruvate
pool is partly isolated from the lactate pool.
L AC T A TE T R AN S PO R T IN
SKELETAL MUSCLE
The transfer of lactate between muscle and blood and
vice versa depends theoretically on two barriers, the
capillary membrane and the sarcolemma. The capillary
wall in general is not considered to form a barrier for
lactate despite the fact that it is unknown which fraction diffuses through the endothelial cleft and which
fraction is taken up by the endothelial cells and released
at the other side. In the latter case, a delay in translocation could occur and transport systems may be
involved. Nevertheless, in general it is assumed that the
sarcolemma is the barrier for muscle lactate inux and
efux. For many years, it was thought that L-lactate
simply diffused across the sarcolemmal membrane.
However, as recently reviewed by Juel (1997) and Juel
& Halestrap (1999), many studies have established that
lactate uptake and release by skeletal muscle is mediated
via membrane-bound carrier proteins. The inhibitor
sensitivity, stereoselectivity, and saturation kinetics of
the monocarboxylate transporter (MCT) have led to the
recognition of in-part facilitated sarcolemma transport
for lactate, co-transported with protons in skeletal
muscle. The MCTs are also responsible for the transport of pyruvate and the ketone bodies acetoacetate, bhydroxybutyrate and acetate. Watt et al. (1988) studied
lactate uptake in the perfused rat hindlimb by the paired
tracer dilution method. Lactate uptake was found to be
pH sensitive and a partially stereospecic, inhibitable
and saturable process. The concentration of L-lactate
for half-maximal rates of lactate inux (the Michaelis
constant, Km) was found to be 21 mM and the maximal

velocity (Vmax) was 0.84 lmol min1 g1 muscle.
However, accurate transport kinetics are difcult to
obtain in intact muscle because of different cell types
and metabolism of the added lactate. To overcome
these problems, model systems of sarcolemmal
membrane vesicles are used. The Km found in those
studies was between 13 and 40 mM. Sarcolemmal giant
vesicles are the only model used so far to study human
skeletal muscle lactate transport (Juel et al. 1994). The
Km and Vmax were 30 mM and 124 lmol min1 g1,
respectively, for equilibrium exchange (concentration at
both sides of the membrane are kept equal; thus values
characterize a combination of external and internal
afnity), and 24 mM (Km) and 63 lmol min1 g1
(Vmax) for zero-trans efux (tracer follows the movement of lactate; values characterize the afnity from the
cis-side). On the basis of the model studies, it seems that
carrier-mediated transport accounts for 5090% of the
total lactate transport and the muscle transport capacity
is high compared with the muscle's ability to produce
lactate. Skeletal muscle contains the MCT isoforms
MCT1 and MCT4. Determination of MCT1 and MCT4
in rat skeletal muscle demonstrated that MCT1 occurs
predominantly in oxidative muscle (McCullagh et al.
1996), whereas the MCT4 content appears to be similar
in various muscles except for a markedly lower content
in soleus (Wilson et al. 1998, Juel & Halestrap 1999). In
humans, a positive relation was observed between
MCT1 density and occurrence of type I bres, whereas
MCT4 density was independent of bre type and the
inter-individual variation was large (Pilegaard et al.
1999). The afnity for lactate is higher for MCT1 (Km
of 5 mM) compared with MCT4 (Km of 20 mM). In
humans an increase in physical activity can improve the
lactate transport capacity of skeletal muscle and is
associated with an increase of sarcolemmal MCT (and
relative increase in MCT1 (Juel & Halestrap 1999). It is
interesting that the type II bres, that seem to produce
more lactate, possess a lower lactate transport capacity.
It has been estimated that a muscle with only type II
bres can be expected to have only one half of the
lactate capacity of a muscle composed of entirely type I
bres (Pilegaard et al. 1994). This seems to be contradictory, but it has been suggested that MCT1 expression in muscle bres may reect the extent to which
transport of lactate into the cell is required for its
oxidation as a respiratory fuel and, in contrast, MCT4 is
most important for lactate efux from the muscles that
rely more on glycolytic metabolism (Juel & Halestrap
1999). The existence of barriers for lactate that may
exist between the different cell compartments is not
discussed. These barriers may be important in the
translocation of lactate from its production to its
consumption site. It has been shown that MCTs are
G Van Hall
present in the mitochondrial membrane suggesting that

these mitochondrial MCTs are not only involved in
pyruvate and ketone body transport but also in transporting lactate into the mitochondria as will be
discussed later.
R O L E O F L D H I N M U S CLE L A CT A TE
M E T AB O L I S M
Lactate dehydrogenase controls the formation of lactate
and may regulate the turnover of lactate in the muscle
cell. LDH is a tetramer composed of either M (muscle)
or H (heart) type which may be combined to form ve
LDH isozymes (LDH15). LDH1 (H4) and LDH2
(H3M) predominantly occur in heart muscle whereas
LDH4 (HM3) and LDH5 (M4) are mostly found in
muscle and liver. In general, it is suggested that heartspecic LDH1,2 favours the reaction of lactate to
pyruvate whereas the LDH4,5 isoform favours lactate
formation (Dawson et al. 1964). Biochemical studies
indicated that LDH was exclusively present in the
cytoplasm (DeDuve et al. 1964). However, later it was
demonstrated that LDH, like other glycolytic enzymes,
exhibits rapidly reversible associations with membraneous subcellular structures such as actin, tropomyosin,
5 troponin and mitochondria (Dolken et al. 1975, Lluis
1985, Nakae & Stoward 1997). This suggested that
LDH exists in both the uid- and the solid-phase of the
cytoplasm and that changes in the equilibrium between
the two phases may play a role in the regulation of lactate
metabolism as the bound and soluble forms exhibit
different kinetic properties (Wilson 1978, Nakae &
Stoward 1997). Microscopic histochemical studies of the
localization of LDH activity in skeletal muscle suggested
that the enzyme was present in the sarcoplasmatic
reticulum, especially in close proximity of glycogen
granules, and less in the ground substance of the sarcoplasm and mitochondrial membranes and cristae (Fahimi
& Amarasingham 1966, Fahimi & Karnovsky 1966, Baba
& Sharma 1971, Deimann et al. 1981). Recently, electron
micrographs of rat skeletal muscle and liver tissue
probed with immunolabelled antibodies for LDH5 and
LDH1 showed both LDH isoforms in the cytosol,
myobrils, and mitochondria (Brooks et al. 1999).
Skeletal muscles possess all isozymes of LDH.
Table 1 gives a summary of investigations that have
studied human mixed muscle LDH activity, the effect
of training on LDH activity and changes in LDH
isozyme pattern, as well as LDH activity in type I and II
bres. Those studies give a uniform and clear picture of
changes in LDH activity and isozyme pattern. The total
LDH activity is lower in type I than in type II bres.
However, the relative contribution of heart-specic
LDH1,2 to the total LDH activity is higher in the type I
compared with the type II bres. Endurance athletes
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650
LDH2
LDH3
LDH4
LDH5
Muscle group and % slow-twitch bres
51 ST slow-twitch bres; ND not detectable. Some values re-calculated with conversion factor for *dry to wet weight muscle of 4.3 and from g protein to g wet weight muscle of 5.9 (Karlsson 1971) and #lkat is
52 lmol s)1. H-LDH LDH1 + 0.75 LDH2 + 0.5 LDH3 + 0.25 LDH1, M-LDH LDH5 + 0.75 LDH4 + 0.5 LDH3 + 0.25 LDH2.
Jansson & Sylen (1986)#
Borges et al. (1989)
Larsson et al. (1978)
Gollnick et al. (1974a, b)

Kanno & Maekawa (1995)
Mygind (1995)
Karlsson et al. (1975)
Apple & Tesch (1989)*
Tesch et al. (1978)
Thorstensson et al. (1977)
Essen-Gustavsson et al. (1984)#
Sjodin et al. (1976)
Linnossier et al. (1997)
LDH1
6%
8%
16%
18%
52%
Vastus lateralis
12%
25%
28%
18%
17%
Gastrocnemius (71% ST)
67 (1 LDH1)
44 (11 LDH1)
21%
28%
23%
16%
13%
180
3%
7%
17%
18%
56%
Vastus lateralis (52% ST)
212
3%
6%
14%
18%
59%
226
Vastus lateralis
293
119 (57 lactatepyruvate)
1434% LDH 1 + 2
)29% LDH 1 + 2
)27% LDH 1 + 2
114 (fast-twitch IIA 9.7, fast-twitch IIB 10.5; slow-twitch 4.9)
66 (fast-twitch IIA 9.2, fast-twitch IIB 10.4; slow-twitch 4.4)
Vastus lateralis
90 (30 H-LDH, 67% M-LDH/total LDH)
Vastus lateralis
352
ND
102
ND
104
3%
70
23%
151
ND
66
3%
144 (64 LDH 1 + 2)
44% LDH 1 + 2
Vastus lat. (49% ST) + deltoideus (57% ST)
65 (39 LDH 1 + 2)
60% LDH 1 + 2
Vastus lat. (71% ST) + gastrocnemius (60% ST)
56 (45 LDH 1 + 2)
80% LDH 1 + 2
Gastrocnemius (79% ST) + deltaoideus (76% ST)
143 (35 LDH 1 + 2)
25% LDH 1 + 2
Triceps brachii (51% ST)
86 (36 LDH 1 + 2)
42% LDH 1 + 2
Soleus (80% ST)
250
11
185 (43 H-LDH), 74% M-LDH/total LDH
264, 2030 year man; 266, 2030 year women; 287, 70 year man; 297, 70 year women) Vastus lateralis (62% ST)
154, 2030 year man; 195, 2030 year women; 181, 70 year man; 219, 70 year women
385
6%
Vastus lateralis
335
16%
Vastus lateralis
393
68%
Myocardium, left ventricle
Total LDH
G Van Hall
Control
M-LDH subunit deciency
2029 years
4049 years
6065 years
Fast-twitch bre
Slow-twitch bre
Untrained
Trained
Heart patients
Untrained
Trained, pre-training
Trained, post-marathon training
Active, pre-training
Active, post-sprint training
Pre-training
Post-sprint training
Aerobic well trained
Pre-moderate trained
Post-anaerobic training
Untrained/sprint trained
Endurance trained
Fast-twitch bre
Slow-twitch bre
Whole muscle
Fast-twitch bre
Slow-twitch bre
Untrained, fast-twitch bre
Untrained, slow-twitch bre
Endurance, fast-twitch bre
Endurance, slow-twitch bre
Strength trained, fast-twitch bre
Strength trained, slow-twitch bre
Weight lifters
Long distance runners
Cross country skiers
Elite cross-country skiers
Apple & Rogers (1986)*
Esbjornsson et al. (1996)#
Subjects/bre type
Study
Table 1 Summary of data of lactate dehydrogenase activities in human skeletal muscle and fast- and slow-twitch muscle bres
have a higher percentage of type I bres and a lower

total LDH activity and a higher relative contribution of
the heart-specic LDH1,2 compared with untrained and
strength-trained athletes. Furthermore, endurance
training causes a decrease in total LDH activity and an
increase in relative activity of LDH1,2. In contrast,
sprint training causes an increase in total LDH activity
and a decrease in relative activity of heart-specic
LDH1,2. The general picture emerging is that type I
bres possess roughly half of the total LDH activity but
contain relatively more LDH1,2 compared with type II
bres. The observed lower LDH activity in endurancetrained vs. untrained and sprint-trained and the
decrease of LDH activity with endurance training
seems to be closely related to the differences in bre
type. However, the relatively higher LDH1,2 content in
type I bres and in skeletal muscle of endurance
athletes as well as the increase in LDH1,2 content with
endurance training has to be interpreted with care.
These changes in general are used to underscore the
enhanced ability of type I bres and endurance-trained
athletes to oxidize lactate compared with type II bres
and untrained and sprint-trained athletes. However,
from Table 1 it seems that although the relative LDH1, 2
content is changing, the absolute specic activity of
LDH1,2 hardly changes. LDH1,2 activity seems to be
well maintained in type I vs. II bres and in the
different kinds of training and with ageing. Even in an
extreme case of M-subunit LDH deciency, LDH1, the
only active LDH isoform present, does not seem to be
up-regulated (Kanno & Maekawa 1995). This implies
that the changes in total LDH activity are mainly in the
muscle type LDH. The negative correlation observed in
top athletes between LDH4,5 activity and running
distance is illustrative (Fig. 3, Saltin et al. 1995). The
Figure 3 Skeletal muscle LDH4,5 isoform activity in top athletes in
relation to their competition track distance. The LDH4,5 activity in

skeletal muscle of top Danish athletes expressed as a function of their
running distance in competition. Data from the study of Saltin et al.
1995).
G Van Hall
differences in LDH1,2 were minimal (4253 lmol min1

g1 muscle) although it seemed positively correlated
with running distance. The physiological signicance of
the adaptation seen with sprint and endurance training
in total LDH activity and isoform pattern and the
differences in total LDH activity between type I and II
is still unclear. This is mainly due to the lack of
knowledge of the role of the different LDH isozymes
and their intracellular distribution.
The muscle LDH4,5 is usually considered to be the
isoform for the formation of lactate and the heart
LDH1,2 for pyruvate formation. One argument for this
assumption is that the substrates, lactate and pyruvate,
have been shown in vitro to suppress LDH1 activity but
not LDH5 (Stambaugh & Post 1966, Battellino et al.
1968). However, inhibition occurs at concentrations of
pyruvate >200500 lM and lactate >50 mM. A 50%
inhibition of the maximal reaction rate is observed
at concentrations of pyruvate 2 mM and lactate
>250 mM. These pyruvate and lactate concentrations
are far higher than have ever been shown for skeletal
muscle in vivo and in situ. The skeletal muscle concentration of pyruvate in humans at rest is 60 lmol kg1
muscle and lactate 1 mmol kg1 muscle and with high
intensity exercise 150 and 2025 mmol kg1 muscle for
pyruvate and lactate, respectively (Karlsson 1971).
Thus, LDH1 substrate inhibition is not likely to occur
in vivo. From Table 2, it can be seen that the Km of
LDH1 for pyruvate is close to the muscle concentration
especially during exercise but the Km of LDH5 is at least
3-fold higher and above the muscle concentration. The
same is true for lactate, with LDH1 having a higher
afnity for lactate than LDH5. However, even the Km
of LDH1 with an average of 7 mM is above the muscle
concentration at rest but well within the range of lactate
concentrations that may occur during exercise. Thus
the in vitro data imply that LDH1 may have the highest
activity for lactate and pyruvate production. However,
in vivo, the amount of LDH1 is low and even in the
untrained, with low relative LDH1 activity, the muscle
is able to consume and produce large amounts of
lactate. Whereas if only LDH1 is present in musclesubunit deciency, about 5% of matched controls total
LDH activity, the muscle lactate accumulation with
ischaemic exercise was also far less, 2.1 mmol kg1
muscle compared with 18.5 mmol kg1muscle in the
patients and controls, respectively (Kanno & Maekawa
1995). This strongly suggests that in vivo both LDH1 and
LDH5 have the same role. The kinetics of LDH in vivo
may be different as binding to subcellular structures has
been suggested to alter its kinetics. Potentially, LDH
kinetics are modied depending on the structure to
which it is attached. This also may imply that total LDH
activity determines the ability of lactate production and
utilization. In addition, local pyruvate and lactate
651
652
Rat skeletal muscle
Li et al. (1986)
LDH5
LDH1
LDH1
LDH5
LDH1
LDH5
LDH1
PL
LP
PL
LP
PL
LP
PL
LP
PL
LP
PL
LP
PL
LP
PL
LP
PL
LP
73
88
60
30
297
81
371
82
59
65
67
)1
0.25
0.12
0.09
3.2
0.09
1.0
0.14
0.35
0.10
0.15
0.06
0.08
)1
20
70
40
25
23
7
14
11
13
Km,lactate
mmol
0.5
50
1.5
150
0.2
25
1.0
150
0.6
40
3
25
0.4
30
3
250
0.7
0.5
30
2.0
100
Optimal conc
mmol
enzyme min , 25 C at pH 7.5.
Km,pyruvate
mmol
PL is the forward reaction from pyruvate to lactate and LP is backwards reaction from lactate to pyruvate, * mol NADH oxidized mol
Rabbit testis
Rabbit muscle
Chicken muscle
Bovine muscle
LDH5
Human liver (periportal)

Mouse skeletal muscle, gastrocnemius
Mouse heart
Rabbit skeletal muscle
LDH1
Pre-exercise
Post-exercise
PL
LP
PL
LP
PL
LP
LP
Vmax
lmol min)1 g)1 muscle
41500*
93400*
45500*
80200*
49400*
Turnover rate
at Vmax*
G Van Hall
Battellino et al. (1968)
Pesce et al. (1967)
Pesce et al. (1964)
Stambaugh & Post (1966)
Nakae & Stoward (1994)
Human skeletal muscle, vastus lateralis
Rat heart muscle
Human skeletal muscle, vastus lateralis
Study
Table 2 Summary of data of lactate dehydrogenase kinetics
concentration may be rather different from the concentrations measured in whole muscle. Thus, compartmentalization of the muscle cell may play an essential role
in lactate metabolism and modifying LDH in such a way
that it produces more lactate at one site and pyruvate at
another.
The mechanism of lactate oxidation is generally
assumed to involve lactate dehydrogenation by cytoplasmic LDH to pyruvate before being transported into
the mitochondria for oxidation. However, there have
been reports that skeletal muscle mitochondria contains
LDH involved in the direct oxidation of lactate
6 (Szczesna-Kaczmarek 1990a, b, Brooks et al. 1999). The
re-oxidation of cytosolic NADH, produced via the
cytoplasmic LDH reaction, by the respiratory chain
mainly proceeds via the malateaspartate cycle.
However, if a mitochondrial LDH is involved in the
direct oxidation of lactate it may be important in the
operation of the hydrogen transport shuttle (SzczesnaKaczmarek 1990a, b). It has been suggested that
mitochondrial LDH could be a potential regulatory
point for lactate oxidation, i.e. transport and oxidation
within the mitochondria (Szczesna-Kaczmarek 1990a,
b, McDermott & Bonen 1992). Accordingly, Brooks
proposed the `intracellular lactate shuttle' (Brooks 1998,
Brooks et al. 1999). In skeletal muscle, lactate is
produced in the cytoplasm via the cytosolic LDH.
Lactate is then transported into the mitochondria via a
MCT. Subsequently, lactate is dehydrogenated to
pyruvate via the mitochondrial LDH and oxidized in
the tricarboxylic acid cycle (TCA-cycle) (see dotted
black lines Fig. 2c). Furthermore, Brooks et al. (1999)
argued that as cytosolic lactate concentration exceeds
that of pyruvate by 10-fold or more, lactate is transported by mitochondrial MCT in quantitatively larger
amounts than pyruvate and thus is the prime substrate
for mitochondrial respiration. However, the existence
of a mitochondrial LDH has been questioned. Popinigis et al. (1991) observed that the rate of L-lactate
oxidation by isolated human skeletal muscle mitochondria was slow and not coupled to ATP synthesis.
When LDH or the cytosolic fraction was added, a high
rate of lactate oxidation was observed. They concluded
that the `direct' oxidation of lactate by isolated mitochondria should be attributed to impurity of mitochondria and contamination of LDH. Furthermore,
they also concluded that for lactate oxidation to occur
in skeletal muscle there is no necessity for a mitochondrial LDH in the light of the high oxidation rates
when the cytosolic fraction was added. This seems to
be conrmed by the observation that isolated mitochondria from mouse quadriceps did not contain LDH
and lactate was not oxidized by the isolated mito7 chondria (Rasmussen H.N. & Rasmussen U.F. 1999,
personal communication).
G Van Hall
A PROPOSAL FOR SKELETAL MUSCLE

L A CT A T E M E T AB O L I S M
Based on an evaluation of existing data, a scheme for
lactate metabolism in skeletal muscle is proposed.
Figure. 2(c) gives a schematic view of muscle lactate
production, consumption, and uptake from the interstitium and subsequent oxidation. To visualize lactate
uxes in mmol min1, a situation is chosen during low
to moderate intensity exercise. In that case the arterial
and venous lactate concentration is nearly identical, i.e.
a small net lactate release or no net exchange. However,
the venous enrichment is far less than the arterial
enrichment, i.e. mutual lactate uptake and release. The
rate of lactate uptake from the microcirculation, via
passive diffusion or facilitated transport via MCT, is
calculated from the difference in the lactate concentration and isotopic enrichment in the vein and artery
(solid pink lines, 2 mmol min1). No estimation can be
made between shunting and the total lactate uptake
(dotted pink line and rates with a question mark). The
lactate shunt represents lactate that goes from the artery
to the vein without entering the intracellular space.
However, a proportion of lactate may enter and again
leave the intracellular space before being metabolized.
Lactate is taken up from the microcirculation and at the
same time intracellularly produced lactate is in part
released from the cell, estimated from the lactate uptake
minus the net lactate balance (solid green lines,
2.1 mmol min1). During low to moderate intensity
exercise the lactate taken up by the muscle cell is nearly
completely oxidized to CO2. No specic role for bre
type or LDH isozyme is implemented in this view as
discussed above. The LDH within the myobril,
potentially associated to or within the sarcoplasmatic reticulum (green tetramer), converts pyruvate to
lactate at rest and at a high rate during exercise. Part of
the intracellularly produced lactate and the extracellular
lactate taken up is oxidized by LDH connected to or
in close proximity with the mitochondrial membrane
(pink tetramer) to pyruvate. The pyruvate is taken up by
the mitochondria for complete oxidation to CO2 in the
pyruvate dehydogenase reaction and in the TCA-cycle.
The role of cytoplasmic `free' LDH can be seen as
LDH that, depending on the subcellular structure it will
associate with, forms pyruvate or lactate. Within the
mitochondria the broken black line and the LDH
represent the potential existence of mitochondrial LDH
(Szczesna-Kaczmarek 1990a, b, Brooks et al. 1999).
Whatever the mechanism of intracellular lactate
handling, the LDH isoform involved, or location within
the cell, lactate is taken up at rest and partially oxidized.
With exercise, lactate uptake increases severalfold and is
nearly completely oxidized. The substantial leg lactate
uptake is illustrated by the fact that at rest leg lactate
653
G Van Hall
uptake was equal to leg glucose uptake. With exercise at

42% VO2max muscle lactate uptake is 2-fold higher than
glucose uptake (Van Hall et al. 1999a, b). Especially
during exercise, lactate is nearly completely oxidized.
This suggests that lactate is an important fuel for
muscular activity. However, at rest, but certainly during
exercise, there is usually a net lactate release or at the
most no net lactate exchange. This implies that, despite
a substantial lactate uptake by the leg, in a net sense
lactate does not add carbon for oxidation, in contrast to
glucose. For each molecule of lactate that enters the
muscle, another leaves the muscle and thus no net ow
from lactate to pyruvate and subsequent oxidation
occur (Wolfe 1992, Landau & Wahren 1992, 1993).
Therefore, the role of lactate in muscle is not the
provision of energy for muscle contraction like glucose.
The role of lactate merely seems to be an intermediate
between glucose and glycogen and to their complete
oxidation in the mitochondria, that can easily shuttle
between the site of production and usage, intra- and
extracellular as well as between tissues as implemented
by the `lactate shuttle' hypothesis (Brooks 1985).
R E F E RE N C E S
Ahlborg, G., Hagenfeldt, L. & Wahren, J. 1975. Substrate
utilization by the inactive leg during one-leg or arm
exercise. J Appl Physiol 39, 718723.
Apple, F.S. & Rogers, M.A. 1986. Skeletal muscle lactate
dehydrogenase isozyme alterations in men and women
marathon runners. J Appl Physiol 61, 477481.
Apple, F.S. & Tesch, P.A. 1989. CK and LD isozymes in
human single muscle bres in trained athletes. J Appl Physiol
66, 27172720.
Baba, N. & Sharma, H.M. 1971. Histochemistry of lactic
dehydrogenase in heart and pectoralis muscles of rat. J Cell
Biol 51, 621635.
Battellino, L.J., Jaime, F.R. & Blanco, A. 1968. Kinetic
properties of rabbit testicular lactate dehydrogenase
isozyme. J Biol Chem 243, 51855192.
Borges, O. & Essen-Gustavsson, B. 1989. Enzyme activities
in type I and II muscle bres of human skeletal muscle in
relation to age and torque development. Acta Physiol Scand
136, 2936.
Brooks, G.A. 1985. Lactate: Glycolytic product and oxidative
substrate during sustained exercise in mammals the `lactate
shuttle'. In: R. Gilles (ed.) Comparitive Physiology and
Biochemistry Current Topics and Trends, Vol. A, Respiration
Metabolism Circulation, pp. 208218. Springer-Verlag, Berlin.
Brooks, G.A. 1998. Mammalian fuel utilization during
sustained exercise. Comp Biochem Physiol B Biochem Mol Biol
120, 89107.
Brooks, G.A., Dubouchaud, H., Brown, M., Sicurello, J.P. &
Butz, C.E. 1999. Role of mitochondrial lactate
dehydrogenase and lactate oxidation in the intracellular
lactate shuttle. Proc Natl Acad Sci 96, 11291134.
654
Carlson, L.A. & Pernow, B. 1959. Oxygen utilization and

lactic acid formation in the legs at rest and during exrecise
in normal subjects and in patients with arteriosclerosis
obliterans. Acta Med Scand 164, 3952.
Chinkes, D.L., Zhang, X.-J., Romijn, J.A., Sakarai, Y. &
Wolfe, R.R. 1994. Measurement of pyruvate and lactate
kinetics across the hindlimb and gut of anesthetized dogs.
Am J Physiol 267, E174E182.
Consoli, A., Nurjhan, N., Reilly, J.J., Bier, D.M. & Gerich, J.E.
1990. Contribution of liver and skeletal muscle to alanine
and lactate metabolism in humans. Am J Physiol 259,
E677E684.
Dawson, D.M., Goodfriend, T.L. & Kaplan, N.O. 1964.
Lactic dehydrogenase: function of the two types. Science
143, 929993.
DeDuve, C., Wattiaux, R. & Baudhuin, P. 1964. Distrubtion
of enzymes between subcellular fractions in animal tissues.
Adv Enzymol 24, 291304.
Deimann, W., Freeman, R. & Fahimi, H.D. 1981. Improved
contrast in cytochemistry of dehydrogenases by scanning
transmission electron microscopy. J Histochem Cyt 29,
678681.
Dolken, G., Leisner, E. & Pette, D. 1975. Immunouorescent
localization of glycolysis and glycolytic enzyme protein and
of malate dehydrogenase isozymes in cross-straited skeletal
muscle and heart of the rabbit. Histochemistry 43, 113121.
Drury, D.R. & Wick, A.N. 1956. Metabolism of lactic acid in
the intact rabbit. Am J Physiol 184, 304308.
Esbjornsson-Liljedahl, M., Holm, I., Sylven, C. & Jansson, E.
1996. Different responses of skeletal muscle following
sprint training in men and women. Eur J Appl Physiol 74,
375383.
Essen-Gustavsson, B. & Henriksson, J. 1984. Enzyme levels
in pools of microdissected human muscle bres of identical
type. Acta Physiol Scand 120, 505515.
Essen, B., Pernow, B., Gollnick, P.D. & Daltin, B. 1975.
Muscle glycogen content and lactate uptake in exercising
muscle. In: H. Howald & J.R. Poortmans (ed.) Metabolic
Adaptation to Prolonged Physical Exercise, pp. 130134.
Birkauser Verlag, Basel.
Fahimi, H.D. & Amarasingham, C.R. 1966. Cytochemical
localization of lactic dehydrogenase in white skeletal
muscle. J Cell Biol 22, 2935.
Fahimi, H.D. & Karnovsky, M.J. 1966. Cytochemical
localization of two glycolytic dehydrogenases in white
skeletal muscle. J Cell Biol 29, 113128.
Fletcher, W.M. & Hopkins, F.G. 1907. Lactic acid in
amphibian muscle. J Physiol 35, 247309.
Freyschuss, U. & Strandell, T. 1967. Limb circulation during
arm and leg exercise in supine position. J Appl Physol 23,
163170.
Gollnick, P.D., Pernow, B., Ess'en, B., Jansson, E. & Saltin, B.
1981. Availability of glycogen and plasma FFA for
substrate utilization in leg muscle of man during exrecise.
Clin Physiol 1, 2742.
Gollnick, P.D., Piehl, K. & Saltin, B. 1974a. Selective glycogen
depletion pattern in human muscle bres after exercise of
varying intensity and varying pedalling rates. J Physiol 241,
4557.
Gollnick, P.D., Sjodin, B., Karlsson, J., Jansson, E. & Saltin,

B. 1974b. Human soleus muscle: a comparison of bre
composition and enzyme activities with other leg muscles.
Pugers Arch 348, 247255.
Green, H.J. & Patla, A.E. 1992. Maximal aerobic power:
neuromuscular and metabolic considerations. Med Sci Sports
Exerc 24, 3846.
Jansson, E. & Sylven, C. 1986. Activities of key enzymes in
the energy metabolism of human myocardial and skeletal
muscle. Clin Physiol 6, 465471.
Jervell, O. 1928. Investigation of the concentration of lactic
acid in blood and urine under physiologic and pathologic
conditions. Acta Med Scand 56, 831838.
Jorfeldt, L. 1970. Metabolism L (+)-lactate human skeletal
muscle during exercise. Acta Physiol Scand 338 (Suppl), 167.
Jorfeldt, L. & Wahren, J. 1970. Human forearm muscle
metabolism during exercise Quantitative aspects of
glucose uptake and lactate production during prolonged
exercise. Scand J Clin Lab Invest 26, 7381.
Juel, C. 1997. Lactate-proton co-transport in skeletal muscle.
Physiol Rev 77, 321358.
Juel, C. & Halestrap, A.P. 1999. Lactate transport in skeletal
muscle Role and regulation of the monocarboxylate
transporter. J Physiol 517, 633642.
Juel, C., Kristiansen, S., Pilegaard, H., Wojtaszewski, J. &
Richter, E.A. 1994. Kinetics of lactate transport in
sarcolemmal giant vesicles obtained from human skeletal
muscle. J Appl Physiol 76, 10311036.
Kanno, T. & Maekawa, M. 1995. Lactate dehydrogenase
M-subunit deciencies: clinical features, metabolic
background, genetic heterogeneities. Mucle & Nerve 3
(Suppl), S54S60.
Karlsson, J. 1971. Lactate and phosphagen concentrations in
working muscle of man. Acta Physiol Scand 358 (Suppl), 172.
Karlsson, J., Diamant, B. & Saltin, B. 1968. Lactate
dehydrogenase activity in muscle after prolonged severe
exercise in man. J Appl Physiol 25, 8891.
Karlsson, J., Hulen, B. & Sjodin, B. 1974. Substrate activation
and product inhibition of LDH activity in human skeletal
muscle. Acta Physiol Scand 92, 2126.
Karlsson, J., Sjodin, B., Thorstensson, A., Hulten, B. & Frith,
K. 1975. LDH isozymes in skeletal muscle of endurance
and strength trained athletes. Acta Physiol Scand 93, 150156.
Landau, B.R. & Wahren, J. 1992. Non productive exchanges:
The use of isotopes gone astray. Metabolism 41, 457459.
Landau, B.R. & Wahren, J. 1993. Reply to the editor.
Metabolism 42, 264266.
Large, V., Soloviev, M., Brunengraber, H. & Beylot, M. 1995.
Lactate and pyruvate isotopic enrichments in plasma tissues
of post-absorptive and starved dogs. Am J Physiol 268,
E880E888.
Larson, L. 1978. Morphological and functional characteristics
of the ageing skeletal muscle in man. Acta Physiol Scand
Suppl. 457.
Li, L., Stratman, F.W. & Lardy, H.A. 1986. Chronic exercise
training alters kinetic properties of rat skeletal muscle and
myocardial lactate dehydrogenase. FEBS Lett 208, 297300.
Linnossier, M.-T. Dormois, D., Perier, C., Frey, J., Geyssant,
A. & Denis, C. 1997. Enzyme adaptions of human skeletal
G Van Hall
muscle during bicycle short-sprint training and detraining.

Acta Physiol Scand 161, 439445.
Lluis, C. 1985. Lactate dehydrogenase binding to the
mitochondrial fraction and to a mitochondrial inhibitor as a
function of the isoenzymatic composition. Int J Biochem 17,
12191226.
McCullagh, K.J.A., Poole, R.C., Halestrap, A.P., O'Brien, M.
& Bonen, A. 1996. Role of the lactate transporter (MCT1)
in skeletal muscle. Am J Physiol 271, E143E150.
McDermott, J.C. & Bonen, A. 1992. Glyconeogenic and
oxidative lactate utilization in skeletal muscle. Can J Physiol
Pharmacol 70, 142149.
Mygind, E. 1995. Fibre characteristics and enzyme levels of
arm and leg muscles in elite cross-country skiers. Scand J
Med Sci Sports 5, 7690.
Nakae, Y. & Stoward, P.J. 1994. The diverse Michaelis
constants and maximum velocities of lactate dehydrogenase
in situ in various type of cell. Histochem J 26, 292297.
Nakae, Y. & Stoward, P.J. 1997. Effects of tissue protectants
on the kinetics of lactate dehydrogenase in cells. J Histochem
Cytochem 45, 14171425.
Newman, E.V., Dill, D.B., Edwards, H.T. & Webster, F.A.
1937. The rate of lactic acid removal in exercise. Am J
Physiol 118, 457462.
Nordheim, K. & Vllenstad, N.K. 1990. Glycogen and lactate
metabolism during low-intensity exercise in man. Acta
Physiol Scand 139, 475484.
Omachi, A. & Lifson, N. 1956. Metabolism of isotopic lactate
by the isolated perfused dog gastrocnemius. Am J Physiol
185, 3540.
Owles, W.H. 1930. Alterations in the lactate acid content of
the blood as a result of light exercise, and associated
changes in the CO2-combining power of the blood and the
alveolar CO2 pressure. J Physiol 69, 214237.
Pagliassotti, M.J. & Donavan, C.M. 1990a. Glycogenesis from
lactate in rabbit skeletal muscle ber types. Am J Physiol
258, R903R911.
Pagliassotti, M.J. & Donovan, C.M. 1990b. Inuence of cell
heterogeneity on skeletal muscle lactate kinetics. Am J
Physiol 258, E625E634.
Pagliassotti, M.J. & Donovan, C.M. 1990c. Role of cell type in
net lactate removal by skeletal muscle. Am J Physiol 258,
E635E642.
Pesce, A., Fondy, T.P., Stolzenbach, F., Castillo, F. & Kaplan,
N.O. 1967. The comparitive enzymolgy of lactic
dehydrogenase. III properties of the H4 and M4 enzymes
from a number of vertebrates. J Biol Chem 242, 21512167.
Pesce, A., McKay, R.H., Stolzenbach, F., Cahn, R.D. &
Kaplan, N.O. 1964. The comparative enzymology of lactic
dehydrogenases. I Properties of the crystalline beef and
chicken enzymes. J Biol Chem 239, 17531761.
Pilegaard, H., Bangsbo, J., Richter, E.A. & Juel, C. 1994.
Lactate transport studied in sarcolemmal giant vesicles
from human muscle biopsies: relation to training status.
J Appl Physiol 77, 18581862.
Pilegaard, H., Terzis, G., Halestrap, A. & Juel, C. 1999.
Distribution of the lactate/H+ transporter isoforms MCT1
and MCT4 in human skeletal muscle. Am J Physiol 276,
E843E848.
655
G Van Hall
Popinigis, J., Antosiewicz, J., Crimi, M., Lenaz, G. &

Wakabayashi, T. 1991. Human skeletal mucle: participation
of different metabolic activities in oxidation of l-lactate.
Acta Biochim Pol 38, 169175.
Rammal, K. & Strom, G. 1949. The rate of lactate utilization
in man during work and at rest. Acta Physiol Scand 17,
453456.
Richardson, R.S., Frank, L.R. & Haseler, L.J. 1998. Dynamic
knee-extensor and cycle exercise: functional MRI of
muscular activity. Int J Sports Med 19, 182187.
Richter, E.A., Kiens, B., Saltin, B., Christensen, N.J. & Savard,
G. 1988. Skeletal muscle glucose uptake during dynamic
exercise in humans: role of muscle mass. Am J Physiol 254,
E555E561.
Romijn, J.A., Chikes, D.L., Schwarz, J.M. & Wolfe, R.R. 1994.
Lactate-pyruate interconversion in blood: implications for
in vivo tracer studies. Am J Physiol 266, R334E340.
Saltin, B., Kim, C.K., Terrados, N., Larsen, H., Svendenhag, J.
& Rolf, C.J. 1995. Morphology, enzyme activities and
buffer capacity in leg muscles of kenyan and scandinavian
runners. Scand J Med Sci Sports 5, 220230.
Sidossis, L.S., Coggan, A.R., Gastadelli, A. & Wolfe, R.R.
1995. A new correction factor for use in a tracer
estimations of plasma fatty acid oxidation. Am J Physiol 269,
E649E656.
Sjodin, B., Thorstensson, A., Frith, K. & Karlsson, J. 1976.
Effect of physical training on LDH activity and LDH
isozyme pattern in human skeletal muscle. Acta Physiol Scand
97, 150157.
Stainsby, W.N. & Welch, H.G. 1966. Lactate metabolism of
contracting dog skeletal muscle in situ. Am J Physiol 211,
177183.
Stambaugh, R. & Post, D. 1966. Substrate and product
inhibition of rabbit muscle lactic dehydrogenase herat (H4)
and muscle (M4) isozymes. J Biol Chem 241, 14621467.
Stanley, W.C., Gertz, E.W., Wisneski, J.A., Neese, R.A.,
Morris, D.L. & Brooks, G.A. 1986. Lactate extraction
during net lactate release in legs of humans during exercise.
J Appl Physiol 60, 11161120.
Szczesna-Kaczmarek, A. 1990a. Direct oxidation of L-Lactate
by mitochodria isolated from different tissues. In:
K. Nazar, R.L. Terjung, H. Kaciuba-U'scilko & L.
Budohoski (eds) International Perpectives in Exercise Physiology,
pp. 130131. Human Kinetics Books, Champaign.
Szczesna-kaczmarek, A. 1990b. L-Lactate oxidation by skeletal
muscle mitochondria. Int J Biochem 22, 617620.
656
Tesch, P., Sjodin, B. & Karlsson, J. 1978. Relationship

between lactate accumulation, LDH activity, LDH isozyme
and bre type distribution in human skeletal muscle.
Acta Physiol Scand 103, 4046.
Thorstensson, A., Sjodin, B., Tesch, P. & Karlsson, J. 1977.
Actomysin ATPase, myokinase, CPK and LDH in human
fast and slow twitch muscle bres. Acta Physiol Scand 99,
225229.
Van Hall, G. 1999. Correction factors for 13C-substrate
oxidation at whole body and muscle level. Proc Nutr Soc 58,
979986.
Van Hall, G., Gonzalez-Alonso, J., Sacchetti, M. & Saltin, B.
1999. Skeletal muscle substrate metabolism during
exercise; methodological considerations. Proc Nutr Soc 58,
899912.
Van Hall, G., Calbet, J.A.L., Sndergaard, H., Saltin, B. 2000.
Skeletal muscle and whole body lactate metabolism at rest
and during exercise in humans. J Physiol, submitted.
Vllestad, N.K. 1985. Effect of varying exercise intensity on
glycogen depletion in human muscle bres. Acta Physiol
Scand 125, 395405.
Watt, P.W., Gladden, L.B., Hundal, H.S. & Crawford, R.E.
1994. Effects of ow and contraction on lactate
transport in the perfused rat hindlimb. Am J Physiol 267,
E7E13.
Watt, P.W., MacLennan, P.A., Hundal, H.S., Kuret, C.M.
& Rennie, M.J. 1988. L(+)-Lactate transport in
perfused rat skeletal muscle: kinetic characteristics and
sensitivity to pH and transport inhibitors. Biochem J
944, 213222.
Wilson, J.E. 1978. Ambiquitous enzymes: variation in
intracellular distribution as a regulatory mechanism. Trends
Biochem Sci 3, 124125.
Wilson, M.C., Jackson, V.N., Heddle, C. et al. 1998. Lactic
acid efux from white skeletal muscle is catalyzed by the
monocarboxylate transporter isoform MCT3. J Biol Chem
273, 1592015926.
Wolfe, R.R. 1992. Radioactive and Stable Isotopes Tracers in
Biomedicine. Principles and Practice of Kinetic Analysis. WileyLiss, Inc, New York.
Wolfe, R.R., Jahoor, F. & Miyoshi, H. 1988. Evaluation of
isotopic equilibration between lactate and pyruvate. Am J
Physiol 254, E532E535.
Zhang, X.J., Baba, H. & Wolfe, R.R. 1993. Further evaluation
of the isotopic equilibration between labeled pyruvate and
lactate. J Nutr Biochem 4, 218221.

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Acta Physiol Scand 2000, 168, 643656

Lactate as a fuel for mitochondrial respiration

Lactate production in skeletal muscle has now been

indicates that lactic acid is a product of its normal

Lactate as a fuel for mitochondria

Acta Physiol Scand 2000, 168, 643656

1975, Gollnick et al. 1981). The uptake of lactate by

Figure 1 Human lactate exchange across a limb. (a) Forearm lactate

net release, uptake and fractional oxidation during 47 min of exercise,

substantially with exercise duration. This seems to be

Acta Physiol Scand 2000, 168, 643656

at the low intensity of 49 W causes an increase in the

Lactate as a fuel for mitochondria

lated and stimulated skeletal muscles, respectively.

Lactate as a fuel for mitochondria

Moreover, during exercise not all muscles of the leg will

Acta Physiol Scand 2000, 168, 643656

has been shown using surface electromyography

Acta Physiol Scand 2000, 168, 643656

Figure 2 Schematic representation of leg lactate handling. (a) Sche-

matic upper leg. Lactate enrichment and concentrations are measured in

Therefore, studies on lactate metabolism across a limb

Lactate as a fuel for mitochondria

tion technique has been used. From those studies the

Lactate as a fuel for mitochondria

intramuscular bicarbonate pools (Van Hall 1999),

Acta Physiol Scand 2000, 168, 643656

lactate. Preliminary data in humans showed that with

Acta Physiol Scand 2000, 168, 643656

constant, Km) was found to be 21 mM and the maximal

Lactate as a fuel for mitochondria

present in the mitochondrial membrane suggesting that

Muscle group and % slow-twitch bres

Jansson & Sylen (1986)#

Borges et al. (1989)

Larsson et al. (1978)

Gollnick et al. (1974a, b)

Karlsson et al. (1975)

Apple & Tesch (1989)*

Tesch et al. (1978)

Thorstensson et al. (1977)

Essen-Gustavsson et al. (1984)#

Sjodin et al. (1976)

Linnossier et al. (1997)

Apple & Rogers (1986)*

Esbjornsson et al. (1996)#

Lactate as a fuel for mitochondria

Acta Physiol Scand 2000, 168, 643656

2000 Scandinavian Physiological Society

Acta Physiol Scand 2000, 168, 643656

have a higher percentage of type I bres and a lower

Figure 3 Skeletal muscle LDH4,5 isoform activity in top athletes in

relation to their competition track distance. The LDH4,5 activity in

Lactate as a fuel for mitochondria

differences in LDH1,2 were minimal (4253 lmol min1

Rat skeletal muscle

enzyme min , 25 C at pH 7.5.

Human liver (periportal)

Battellino et al. (1968)

Pesce et al. (1967)

Pesce et al. (1964)

Stambaugh & Post (1966)

Nakae & Stoward (1994)

Human skeletal muscle, vastus lateralis