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The Journal of Experimental Biology 204, 3133–3139 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 JEB3288
Muscle tissue adaptations to hypoxia Hans Hoppeler* and Michael Vogt Department of Anatomy, University of Bern, Bühlstrasse 26, CH-3000 Bern 9, Switzerland *e-mail:
[email protected]
Accepted 2 July 2001 Summary Studies have therefore been conducted in which subjects This review reports on the effects of hypoxia on human were exposed to hypoxia only during exercise sessions. In skeletal muscle tissue. It was hypothesized in early reports this situation, the potentially negative effects of permanent that chronic hypoxia, as the main physiological stress hypoxic exposure and other confounding variables related during exposure to altitude, per se might positively affect to exposure to high altitude could be avoided. Training in muscle oxidative capacity and capillarity. However, it is hypoxia results, at the molecular level, in an upregulation now established that sustained exposure to severe hypoxia of the regulatory subunit of hypoxia-inducible factor-1 has detrimental effects on muscle structure. Short-term (HIF-1). Possibly as a consequence of this upregulation of effects on skeletal muscle structure can readily be observed HIF-1, the levels mRNAs for myoglobin, for vascular after 2 months of acute exposure of lowlanders to severe endothelial growth factor and for glycolytic enzymes, such hypoxia, e.g. during typical mountaineering expeditions to as phosphofructokinase, together with mitochondrial and the Himalayas. The full range of phenotypic malleability of capillary densities, increased in a hypoxia-dependent muscle tissue is demonstrated in people living permanently manner. Functional analyses revealed positive effects on at high altitude (e.g. at La Paz, 3600–4000 m). In addition, . VO∑max (when measured at altitude) on maximal power there is some evidence for genetic adaptations to hypoxia in high-altitude populations such as Tibetans and Quechuas, output and on lean body mass. In addition to the positive who have been exposed to altitudes in excess of 3500 m effects of hypoxia training on athletic performance, there is for thousands of generations. The hallmark of muscle some recent indication that hypoxia training has a positive adaptation to hypoxia in all these cases is a decrease in effect on the risk factors for cardiovascular disease. muscle oxidative capacity concomitant with a decrease in aerobic work capacity. It is thought that local tissue hypoxia is an important adaptive stress for muscle tissue in Key words: skeletal muscle, hypoxia, capillary, mitochondria, human. exercise training, so these results seem contra-intuitive.
Introduction The purpose of the following review is to describe the structural adaptations of skeletal muscle tissue in humans in response to temporary or permanent exposure to altitude. Altitude, and in particular the hypoxia that poses its main physiological challenge, can be seen as a stressful environmental condition to which organisms have a capacity to respond by adaptation (Bligh and Johnson, 1973). In the context of this review, we will explore the phenotypic plasticity of skeletal muscle tissue with regard to altitude (acclimatization). Limited evidence is presented that, in some high-altitude populations, some adaptations to altitude may have become genetically fixed. In the context of altitude research, the term acclimation is used to describe phenotypic alterations that are the response to simulated as opposed to real exposure to high altitude (Banchero, 1987). This review will also cover results of acclimation studies in which hypoxia was used during exercise training sessions in humans with the aim of improving athletic performance.
The first report on adaptations of muscle tissue to hypoxia, notably in humans, is the landmark paper of Reynafarje (Reynafarje, 1962), who found oxidative capacity and myoglobin concentration to be elevated in biopsies of sartorius muscle from permanent high-altitude (4400 m) residents compared with sea-level dwellers. Before that, Valdivia (Valdivia, 1958) presented evidence for a significantly increased (by approximately 30 %) capillary supply to skeletal muscle tissue in guinea pigs native to the Andes compared with animals raised at sea level. The data presented in these papers influenced the way in which physiologists thought about the effects of hypoxia on muscle tissue and, as a consequence, also influenced the design of experiments for almost 30 years. Hochachka et al. (Hochachka et al., 1983) condensed the concepts with which high-altitude adaptations in muscle tissue were discussed in what he called an interpretive hypothesis. He defined as the key problem of the organism in hypoxia: ‘to maintain an acceptable high scope for aerobic metabolism in
3134 H. Hoppeler and M. Vogt the face of the reduced oxygen availability in the atmosphere’. According to this hypothesis, this is achieved by increasing the activities of oxidative enzymes to augment the maximum flux capacity of aerobic metabolism. Supporting a larger oxidative capacity would, in turn, necessitate adaptations of the oxygentransfer system such as an increased capillarity, shorter diffusion distances and a higher myoglobin concentration in muscle. Hochachka et al. (Hochachka et al., 1983) were able to explain the observations of the classical papers and many subsequent studies within a coherent conceptual framework. However, doubt was cast on this unifying view of hypoxia adaptations by the review of Banchero (Banchero, 1987). Reporting on animal studies with hypoxia exposures of more than 2 weeks, he came to the conclusion that skeletal muscle capillarity does not respond to normothermic hypoxia even when the muscle is active. He criticized most hypoxia studies on the grounds that they did not control for activity or temperature and that both these factors could be major determinants of muscle adaptive events during hypoxia. It is unclear at present to what extent species differences in responses to hypoxia might be responsible for divergent experimental outcomes when the effects of hypoxia are compared across species. Muscle structure in lowlanders exposed to acute hypoxia for up to 2 months A dramatic and consistent consequence of severe altitude exposure, such as during an expedition to the Himalayas (Fig. 1), is a loss of body mass (typically between 5 and 10 %) and a similar loss of muscle volume (see Hoppeler et al., 1990). These decreases in muscle and body mass do not seem to be due to malabsorption (Kayser et al., 1992) and may be circumvented when optimal housing and nutritional conditions 5
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Fig. 1. V˙O2max measured before, during the course of and after a typical exposure to altitude for an expedition to Mount Everest base camp (open symbols, sea-level measurements; filled symbols, altitude measurements. Values are means ± S.E.M. for 10 subjects. The asterisk demonstrates that the pre-exposure value is significantly different from all other measurements (P
