Exp Physiol 101.

1 (2016) pp 23–27 23

Symposium Report

Energy metabolism and the high-altitude environment

Andrew J. Murray
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

New Findings
r What is the topic of this review?
This report describes changes in cardiac and skeletal muscle energy metabolism that occur
with exposure to high altitude and considers possible underlying mechanisms.
r What advances does it highlight?
In the human heart, sustained hypoxia at high altitude or shorter-term normobaric hypoxia
result in a loss of cardiac energetic reserve. In the hypoxic rat heart, fatty acid oxidation
and respiratory capacity fall. In skeletal muscle, prolonged exposure to extreme high altitude
Experimental Physiology

results in the loss of mitochondrial density, but even at more moderate high altitude the
respiratory capacity may be suppressed. Evidence from cells, genetically modified mice and
high-altitude-adapted Tibetans suggests a possible mechanistic role for the hypoxia-inducible
factor pathway.

At high altitude the barometric pressure falls, challenging oxygen delivery to the tissues. Thus,
whilst hypoxia is not the only physiological stress encountered at high altitude, low arterial
P O2 is a sustained feature, even after allowing adequate time for acclimatization. Cardiac and
skeletal muscle energy metabolism is altered in subjects at, or returning from, high altitude.
In the heart, energetic reserve falls, as indicated by lower phosphocreatine-to-ATP ratios. The
underlying mechanism is unknown, but in the hypoxic rat heart fatty acid oxidation and
respiratory capacity are decreased, whilst pyruvate oxidation is also lower after sustained hypoxic
exposure. In skeletal muscle, there is not a consensus. With prolonged exposure to extreme
high altitude (>5500 m) a loss of muscle mitochondrial density is seen, but this was not
observed in a simulated ascent of Everest in hypobaric chambers. At more moderate high
altitude, decreased respiratory capacity may occur without changes in mitochondrial volume
density, and fat oxidation may be downregulated, although this is not seen in all studies. The
underlying mechanisms, including the possible role of hypoxia-signalling pathways, remain to
be resolved, particularly in light of confounding factors in the high-altitude environment. In
high-altitude-adapted Tibetan natives, however, there is evidence of natural selection centred
around the hypoxia-inducible factor pathway, and metabolic features in this population (e.g.
low cardiac phosphocreatine-to-ATP ratios, increased cardiac glucose uptake and lower muscle
mitochondrial densities) share similarities with those in acclimatized lowlanders, supporting a
possible role for the hypoxia-inducible factor pathway in the metabolic response of cardiac and
skeletal muscle energy metabolism to high altitude.

(Received 12 July 2015; accepted after revision 20 August 2015; first published online 28 August 2015)
Corresponding author A. J. Murray: Department of Physiology, Development and Neuroscience, University of
Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: ajm267@cam.ac.uk


C 2015 The Authors. Experimental Physiology 
C 2015 The Physiological Society DOI: 10.1113/EP085317
24 A. J. Murray
Introduction
The defining feature of the high-altitude environment
is sustained hypobaric hypoxia. Whilst the atmosphere
is 21% oxygen at all altitudes, barometric pressure falls
upon ascent, and with it inspired P O2 , challenging oxygen
delivery to the tissues. The majority of the world’s
population inhabits regions below 1000 m elevation, but
nevertheless, our species has a remarkable capacity for
hypoxia tolerance. Most notably, over tens of thousands
of years some high-altitude populations have adapted
to life in this environment, with genetic signatures
revealing natural selection around hypoxia-sensing
pathways (Bigham & Lee, 2014). Approximately 140
million people live above 2500 m, but around 40 million
others venture into high-altitude regions each year for
work or leisure (West et al. 2007). These lowlanders
experience a physiological response upon ascent, which
has been well documented elsewhere and includes
ventilatory, cardiovascular and erythropoietic aspects
(West et al. 2007). Even with adequate acclimatization,
energy metabolism is altered in human heart and skeletal
muscle. This might indicate a failure to compensate fully
or may itself form part of the acclimatization process, but it
involves changes in gene expression and thus appears to be
a regulated response. The positive aspects of high-altitude
acclimatization, most notably decreased susceptibility
to acute mountain sickness, also contrast with the
less well-understood phenomenon of high-altitude
deterioration, which occurs with prolonged exposure to
extreme high altitude (>5500 m) and is characterized by
lethargy, fatigue and muscle wasting (Ward, 1954).
Hypoxia is not, however, the only stress encountered
at altitude (West et al. 2007). Temperature falls with
increasing elevation, whilst absolute humidity is extremely
low and exposure to solar/ultraviolet radiation high.
Visitors frequently experience gastrointestinal upset and
appetite loss, which could result from the hypoxia itself,
but may be exacerbated by infection, particularly in
developing countries. In addition, activity levels are
often altered, as oxygen delivery limits exercise capacity
and motivation falls; thus, individuals may undergo
detraining.
In light of these confounding factors, the high-altitude
environment is not a perfect setting in which to study
the physiological response to hypoxia alone, although
other contexts (e.g. confinement to normobaric hypoxia
chambers) have limitations too. The study of humans
(and other animals) at altitude is nevertheless a valuable
research endeavour. First, with increasing numbers of
people visiting mountainous regions, an understanding
of the integrated response to altitude is vital, particularly
the interindividual variation in this response, which is not
fully explained by classic descriptions of acclimatization.
Second, the study of extreme environment physiology
Exp Physiol 101.1 (2016) pp 23–27
and a consideration of the limits of human tolerance is a
stimulating intellectual challenge in its own right and adds
to our understanding of homeostatic regulation. Third,
exposure to sustained physiological challenge in extreme
environments has been proposed as a possible analogue
of human disease (Grocott et al. 2007), and whilst this
approach risks overinterpretation of similarities between
settings it does allow for the study of preselected and
otherwise healthy cohorts in adverse conditions. Finally,
the natural experiment of high-altitude adaptation in
East Africa, the Tibetan Plateau and the Andes offers an
invaluable scenario in which to study human genetics and
natural selection (Bigham & Lee, 2014).
Cardiac energy metabolism at high altitude
In subjects returning from Everest Base Camp
(5300 m), cardiac phosphocreatine-to-ATP ratios
(PCr/ATP; measured using 31 P NMR spectroscopy)
decreased by 18% (Holloway et al. 2011b), indicating a
loss of energetic reserve. This was accompanied by altered
diastolic function and a loss of left ventricular (LV) mass,
but all measures returned to normal after 6 months back
at sea level. In an accompanying study, shorter term
exposure to normobaric hypoxia (20 h, 50–60 mmHg
atmospheric P O2 ) also elicited a loss of cardiac energetics
(Holloway et al. 2011a). The PCr/ATP fell by 15%,
and echocardiographic measurements suggested a mild
alteration in diastolic function. Whilst different cellular
mechanisms may underlie the observations in these
studies, in both instances exposure to a hypoxic stimulus
resulted in a loss of cardiac energetic reserve. This is
reminiscent of findings in the hearts of highland-dwelling
Sherpas, who had lower a cardiac PCr/ATP than
lowlanders, which persisted even after 4 weeks spent
de-acclimatizing at low altitude (Hochachka et al. 1996).
Studies of rats in hypoxic chambers have helped to
elucidate the cardiac metabolic response to sustained
environmental hypoxia. In rats, exposure to 11% O2
for 1 week resulted in decreased LV expression of genes
regulated by the fatty acid (FA)-activated transcription
factor peroxisome proliferator-activated receptor α
(PPARα), including carnitine palmitoyl-transferase 1,
pyruvate dehydrogenase kinase 4 and uncoupling
protein 3, suggesting downregulation of FA oxidation
and increased pyruvate oxidation (Essop et al. 2004).
Whilst this was associated with decreased O2 consumption
and ATP synthesis, mitochondrial coupling was preserved
(Essop et al. 2004). After 12 weeks, expression of FA
oxidation genes decreased in both ventricles, whereas
expression of pyruvate dehydrogenase kinase 4 mRNA
increased in the LV, suggesting inhibition of pyruvate
oxidation with more sustained exposure (Adrogue et al.
2005).

C 2015 The Authors. Experimental Physiology 
C 2015 The Physiological Society
Exp Physiol 101.1 (2016) pp 23–27 Energy metabolism at high altitude
In support of this suggestion, 2 weeks at 11% O2
decreased respiration rates with FA substrates (palmitoyl-
carnitine or palmitoyl-CoA) and pyruvate in both
subsarcolemmal and intermyofibrillar subpopulations
of mitochondria from rat LV/septum. Curiously,
O2 consumption with the electron transport chain
complex I substrate, glutamate, was lowered in hypoxic
subsarcolemmal but not intermyofibrillar mitochondria,
alongside decreased complex I protein (Heather et al.
2012). Work from our laboratory confirmed a loss of
complex I-supported respiration, FA oxidation capacity
and ATP levels in the LV of hypoxic rats (13% O2 ,
2 weeks), alongside increased oxidative stress. All changes
were prevented, however, by dietary supplementation
with a moderate dose of nitrate, which improved tissue
oxygenation, possibly via improved blood flow and/or
tissue metabolic efficiency (Ashmore et al. 2014).
In the hypoxic rat heart, therefore, FA oxidation
is downregulated, with a loss of respiratory capacity
in the LV. Pyruvate oxidation may also be inhibited,
suggesting increased glycolysis. Whilst little is known
about substrate metabolism in the hypoxic human heart,
glucose uptake was higher in the hearts of highland natives
than lowlanders (Holden et al. 1995).
Skeletal muscle energy metabolism at high altitude
In comparison with studies of cardiac energy metabolism,
more numerous investigations have been carried out
into the metabolic response of human skeletal muscle
at altitude, perhaps owing to the relative ease of
obtaining biopsies. This has not, however, resulted in
a consistent picture, perhaps because of varied ascent
profiles, training status and exposure to confounding
features of the high-altitude environment. In a recent
review, we attempted to find consensus amongst studies
of metabolism in human muscle at altitude, plus humans
and rodents in hypoxia chambers (Horscroft & Murray,
2014). Considering only human studies, a picture emerges
in which the duration and degree of exposure to hypoxia
may be crucial.
With prolonged exposure to extreme high altitude, as
experienced on Himalayan mountaineering expeditions, a
loss of muscle mitochondrial volume density occurs, with
the greatest loss from the subsarcolemmal population of
mitochondria (Hoppeler et al. 1990; Levett et al. 2012).
It is not clear whether this is caused by hypoxia (or the
accompanying oxidative stress) or is instead a detraining
response, but notably, the subsarcolemmal population of
mitochondria is more susceptible to changes in volume
density during training studies at sea level (Desplanches
et al. 1993). The response does, however, appear to be
regulated, with altered expression of genes including
a 50% loss of mRNA of the mitochondrial biogenesis
factor, peroxisome proliferator-activated receptor gamma

C 2015 The Authors. Experimental Physiology 
C 2015 The Physiological Society
25
co-activator 1 alpha (PGC1α), and corresponding changes
in protein levels of metabolic regulators and enzymes
(Levett et al. 2012).
During Operation Everest II (a gradual decompression
to the equivalent of 8840 m in a chamber), however,
no such change in mitochondrial volume density was
observed (Green et al. 1989). This simulation took place
over a slightly shorter time frame than a classic Everest
ascent, but with the subjects confined to a chamber a
greater loss of mitochondria might have been expected
due to detraining. The discrepancy has not been resolved,
but whatever the cause the loss of mitochondria at
extreme altitude fits neatly alongside Ward’s description
of high-altitude deterioration (Ward, 1954).
At more moderate high altitude, even with prolonged
exposure, no such loss in mitochondrial volume density
occurs, although notably, lower muscle mitochondrial
densities have been reported in some high-altitude natives
(Kayser et al. 1991, 1996). Changes in muscle respiratory
function occur at more moderate altitudes, but again
this may be dependent on the extent of exposure. Two
similar high-resolution respirometry studies by Lundby
and co-workers described a loss of respiratory capacity
and improved coupling following 28 days at 3454 m
(Jacobs et al. 2012), but no changes after 9–11 days at
4559 m (Jacobs et al. 2013). Meanwhile, some studies have
reported the downregulation of FA oxidative enzymes
with prolonged exposure to altitudes between 4300 and
8848 m (Roberts et al. 1996; Levett et al. 2012), although
no such differences were found in another study at
5250 m (Mizuno et al. 2008). Despite changes in resting
metabolites, however, muscle PCr recovery half-times
following an exercise challenge were remarkably well
preserved in subjects returning either from Everest Base
Camp or the summit, indicating that muscle capacity for
ATP synthesis may in fact be spared (Edwards et al. 2010).
The recent discovery of genetic selection on the
PPARA gene in Tibetan populations (Simonson et al.
2010) suggests that altered FA metabolism may be a
feature of long-term adaptation to high altitude, because
the gene encodes the FA-activated transcription factor
and regulator of FA oxidation, PPARα. The functional
significance of this polymorphism is currently unresolved,
but recent work carried out by our group, in collaboration
with Professor Erich Gnaiger and Dr Julian Griffin, has
used high-resolution respirometry and metabolic profiling
to investigate FA metabolism in the muscles of lowlanders
and Sherpas at altitudes up to 5300 m (Gilbert-Kawai et al.
2015).
Mechanisms, unanswered questions and future
directions
What mechanisms might underlie the changes in heart
and muscle metabolism at altitude? Hypoxia-signalling
26 A. J. Murray
pathways are an intuitive possibility. Many of the metabolic
changes reported in humans at altitude or in the hypoxic
rat heart (e.g. pyruvate dehydrogenase inhibition and
decreased mitochondrial respiration) have also been
observed in hypoxic cells in culture and are associated
with stabilization of the hypoxia-inducible factor (HIF)
family of transcription factors (reviewed by Murray, 2009).
Adding support to a HIF-driven mechanism, oxidative
metabolism, and thus exercise capacity, were augmented in
the gastrocnemius muscle of mice in which skeletal muscle
HIF-1α had been selectively deleted (Mason et al. 2007).
The effects of the HIF pathway on muscle metabolism are
outlined elsewhere in this issue of Experimental Physiology
by Dr Helene Rundqvist (Lindholm et al. 2016).
An alternative possibility to low muscle P O2 per se
could be reactive oxygen species (ROS)-mediated effects,
because mitochondrial ROS production increases in
hypoxia (Guzy & Schumacker, 2006) and is modelled to
increase sharply in muscle above altitudes corresponding
to those of the highest permanent human settlements
(Cano et al. 2014). Reactive oxygen species have sometimes
been described as indiscriminate mediators of damage
to lipids, protein and DNA, and this may be the case
when generated in large quantities, but at more moderate
concentrations they play an important signalling
role within the cell and can, for instance, bring about
stabilization of HIF-1α (Guzy & Schumacker, 2006).
Reactive oxygen species-mediated effects, particularly
those that occur via interactions with HIF, are difficult to
separate from hypoxia-mediated responses, although the
use of antioxidants in studies of hypoxia can help. Indeed,
in contrast to the notion of ROS-mediated suppression of
mitochondrial function, antioxidant therapy was found to
suppress muscle mitochondrial biogenesis in response to
training (Gomez-Cabrera et al. 2008). This might suggest
that transient production of ROS during training (possibly
as a result of acute hypoxia due to high rates of muscle
O2 consumption) may elicit training-induced changes, in
agreement with a signalling role. Moreover, as outlined
elsewhere in this issue of Experimental Physiology by Prof.
Carsten Lundby (Lundby & Jacobs, 2016), the response to
hypoxia may in fact mediate some aspects of endurance
training in muscle.
Conclusions
The duration and degree of hypoxic exposure are critical
to the metabolic response of skeletal muscle, with the
response to acute hypoxia during exercise or relatively
mild hypoxia at lower altitudes differing from that
seen with more sustained and severe hypoxia following
prolonged stays at higher altitudes. In the human heart,
a loss of energetics is common to both short-term and
long-term exposure, although the underlying mechanisms
Exp Physiol 101.1 (2016) pp 23–27
are probably distinct. Confounding factors such as changes
in activity or diet at altitude cannot, however, be ruled
out. Future studies combining different hypoxic protocols
with controlled activity/inactivity and diet could thus
be revealing and have the potential to elucidate the
mechanisms underlying the metabolic changes in human
heart and muscle at high altitude.
References
Adrogue JV, Sharma S, Ngumbela K, Essop MF & Taegtmeyer
H (2005). Acclimatization to chronic hypobaric hypoxia is
associated with a differential transcriptional profile between
the right and left ventricle. Mol Cell Biochem 278, 71–78.
Ashmore T, Fernandez BO, Branco-Price C, West JA, Cowburn
AS, Heather LC, Griffin JL, Johnson RS, Feelisch M &
Murray AJ (2014). Dietary nitrate increases arginine
availability and protects mitochondrial complex I and
energetics in the hypoxic rat heart. J Physiol 592,
4715–4731.
Bigham AW & Lee FS (2014). Human high-altitude adaptation:
forward genetics meets the HIF pathway. Genes Dev 28,
2189–2204.
Cano I, Selivanov V, Gomez-Cabrero D, Tegnér J, Roca J,
Wagner PD & Cascante M (2014). Oxygen pathway modeling
estimates high reactive oxygen species production above the
highest permanent human habitation. PLoS One 9, e111068.
Desplanches D, Hoppeler H, Linossier MT, Denis C, Claassen
H, Dormois D, Lacour JR & Geyssant A (1993). Effects of
training in normoxia and normobaric hypoxia on human
muscle ultrastructure. Pflugers Arch 425, 263–267.
Edwards LM, Murray AJ, Tyler DJ, Kemp GJ, Holloway CJ,
Robbins PA, Neubauer S, Levett D, Montgomery HE,
Grocott MP & Clarke K; Caudwell Xtreme Everest Research
Group (2010). The effect of high-altitude on human skeletal
muscle energetics: P-MRS results from the Caudwell Xtreme
Everest expedition. PLoS One 5, e10681.
Essop MF, Razeghi P, McLeod C, Young ME, Taegtmeyer H &
Sack MN (2004). Hypoxia-induced decrease of UCP3 gene
expression in rat heart parallels metabolic gene switching
but fails to affect mitochondrial respiratory coupling.
Biochem Biophys Res Commun 314, 561–564.
Gilbert-Kawai E, Sheperdigian A, Adams T, Mitchell K, Feelisch
M, Murray A, Peters M, Gilbert-Kawai G, Montgomery H,
Levett D, Kumar R, Mythen M, Grocott M & Martin D
(2015). Design and conduct of Xtreme Everest 2: an
observational cohort study of Sherpa and lowlander
responses to graduated hypobaric hypoxia. F1000Res 4, 90.
Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A,
Borras C, Pallardo FV, Sastre J & Viña J (2008). Oral
administration of vitamin C decreases muscle mitochondrial
biogenesis and hampers training-induced adaptations in
endurance performance. Am J Clin Nutr 87, 142–149.
Green HJ, Sutton JR, Cymerman A, Young PM & Houston CS
(1989). Operation Everest II: adaptations in human skeletal
muscle. J Appl Physiol 66, 2454–2461.
Grocott M, Montgomery H & Vercueil A (2007). High-altitude
physiology and pathophysiology: implications and relevance
for intensive care medicine. Crit Care 11, 203.

C 2015 The Authors. Experimental Physiology 
C 2015 The Physiological Society
Exp Physiol 101.1 (2016) pp 23–27 Energy metabolism at high altitude
Guzy RD & Schumacker PT (2006). Oxygen sensing by
mitochondria at complex III: the paradox of increased
reactive oxygen species during hypoxia. Exp Physiol 91,
807–819.
Heather LC, Cole MA, Tan JJ, Ambrose LJ, Pope S, Abd-Jamil
AH, Carter EE, Dodd MS, Yeoh KK, Schofield CJ & Clarke K
(2012). Metabolic adaptation to chronic hypoxia in cardiac
mitochondria. Basic Res Cardiol 107, 268.
Hochachka PW, Clark CM, Holden JE, Stanley C, Ugurbil K &
Menon RS (1996). 31 P magnetic resonance spectroscopy of
the Sherpa heart: a phosphocreatine/adenosine triphosphate
signature of metabolic defense against hypobaric hypoxia.
Proc Natl Acad Sci USA 93, 1215–1220.
Holden JE, Stone CK, Clark CM, Brown WD, Nickles RJ,
Stanley C & Hochachka PW (1995). Enhanced cardiac
metabolism of plasma glucose in high-altitude natives:
adaptation against chronic hypoxia. J Appl Physiol 79,
222–228.
Holloway C, Cochlin L, Codreanu I, Bloch E, Fatemian M,
Szmigielski C, Atherton H, Heather L, Francis J, Neubauer S,
Robbins P, Montgomery H & Clarke K (2011a). Normobaric
hypoxia impairs human cardiac energetics. FASEB J 25,
3130–3135.
Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE,
Codreanu I, Hopwood N, Johnson AW, Rider OJ, Levett DZ,
Tyler DJ, Francis JM, Neubauer S, Grocott MP & Clarke K;
Caudwell Xtreme Everest Research Group (2011b). Cardiac
response to hypobaric hypoxia: persistent changes in cardiac
mass, function, and energy metabolism after a trek to Mt.
Everest Base Camp. FASEB J 25, 792–796.
Hoppeler H, Howald H & Cerretelli P (1990). Human muscle
structure after exposure to extreme altitude. Experientia 46,
1185–1187.
Horscroft JA & Murray AJ (2014). Skeletal muscle energy
metabolism in environmental hypoxia: climbing towards
consensus. Extrem Physiol Med 3, 19.
Jacobs RA, Boushel R, Wright-Paradis C, Calbet JA, Robach P,
Gnaiger E & Lundby C (2013). Mitochondrial function in
human skeletal muscle following high-altitude exposure. Exp
Physiol 98, 245–255.
Jacobs RA, Siebenmann C, Hug M, Toigo M, Meinild AK &
Lundby C (2012). Twenty-eight days at 3454-m altitude
diminishes respiratory capacity but enhances efficiency in
human skeletal muscle mitochondria. FASEB J 26,
5192–5200.
Kayser B, Hoppeler H, Claassen H & Cerretelli P (1991).
Muscle structure and performance capacity of Himalayan
Sherpas. J Appl Physiol 70, 1938–1942.
Kayser B, Hoppeler H, Desplanches D, Marconi C, Broers B &
Cerretelli P (1996). Muscle ultrastructure and biochemistry
of lowland Tibetans. J Appl Physiol 81, 419–425.
Levett DZ, Radford EJ, Menassa DA, Graber EF, Morash AJ,
Hoppeler H, Clarke K, Martin DS, Ferguson-Smith AC,
Montgomery HE, Grocott MP & Murray AJ; Caudwell
Xtreme Everest Research Group (2012). Acclimatization of
skeletal muscle mitochondria to high-altitude hypoxia
during an ascent of Everest. FASEB J 26, 1431–1441.

C 2015 The Authors. Experimental Physiology 
C 2015 The Physiological Society
27
Lindholm ME & Rundqvist H (2016). Skeletal muscle
hypoxia-inducible factor-1 and exercise. Exp Physiol 101,
28–32.
Lundby C & Jacobs RA (2016). Adaptations of skeletal muscle
mitochondria to exercise training. Exp Physiol 101,
17–22.
Mason SD, Rundqvist H, Papandreou I, Duh R, McNulty WJ,
Howlett RA, Olfert IM, Sundberg CJ, Denko NC, Poellinger
L & Johnson RS (2007). HIF-1α in endurance training:
suppression of oxidative metabolism. Am J Physiol Regul
Integr Comp Physiol 293, R2059–R2069.
Mizuno M, Savard GK, Areskog NH, Lundby C & Saltin B
(2008). Skeletal muscle adaptations to prolonged exposure
to extreme altitude: a role of physical activity? High Alt Med
Biol 9, 311–317.
Murray AJ (2009). Metabolic adaptation of skeletal muscle to
high altitude hypoxia: how new technologies could resolve
the controversies. Genome Med 1, 117.
Roberts AC, Butterfield GE, Cymerman A, Reeves JT, Wolfel EE
& Brooks GA (1996). Acclimatization to 4,300-m altitude
decreases reliance on fat as a substrate. J Appl Physiol 81,
1762–1771.
Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon
DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT & Ge R
(2010). Genetic evidence for high-altitude adaptation in
Tibet. Science 329, 72–75.
Ward M (1954). High altitude deterioration. Proc R Soc Lond B
Biol Sci 143, 40–42.
West JB, Schoene RB & Milledge JS (2007). High Altitude
Medicine and Physiology. Hodder Arnold, London.
Additional information
Competing interests
None declared.
Funding
This report received no direct funding.
Acknowledgements
The author wishes to thank the many colleagues and
collaborators with whom he has had the pleasure of carrying
out research in this area, but particularly Tom Ashmore,
Kieran Clarke, Lindsay Edwards, Martin Feelisch, Edward
Gilbert-Kawai, Erich Gnaiger, Julian Griffin, Mike Grocott,
Cameron Holloway, Hans Hoppeler, James Horscroft, Randall
Johnson, Aleksandra Kotwica, Verena Laner, Denny Levett,
Daniel Martin and Hugh Montgomery. The author also thanks
the British Heart Foundation, Research Councils UK, BBSRC,
Action Medical Research, Oroboros Instruments and the WYNG
Foundation for supporting research in his laboratory.