Muscle structure and performance capacity of Himalayan Sherpas

Kayser, Bengt; Hoppeler, H.; Claassen, Horst; Cerretelli, Paolo

doi:10.1152/jappl.1991.70.5.1938

Cited by 116 publications

(106 citation statements)

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“…At baseline, Sherpas had 26% lower muscle CS activity than Lowlanders (P < 0.05; Fig. 3A), in agreement with findings of 17-33% lower mitochondrial volume density in Sherpa vastus lateralis compared with Lowlanders (22). In accordance with lower CS activity, concentrations of 6-and 5-carbon intermediates downstream of CS (citrate, aconitate, isocitrate, and α-ketoglutarate) were lower in Sherpas than Lowlanders (P < 0.001).…”

Section: Resultssupporting

confidence: 82%

“…In Lowlander muscle, mitochondrial density declines with sustained exposure to extreme altitude (16)(17)(18), whereas exposure to more moderate high altitude is associated with a reprogramming of muscle metabolism (19) even without altered mitochondrial density (20), including down-regulation of electron transfer complexes (19) and tricarboxylic acid (TCA) cycle enzymes (21), loss of fatty acid oxidation (FAO) capacity (19,20), and improved oxidative phosphorylation (OXPHOS) coupling efficiency (20). Sherpas have lower muscle mitochondrial densities than unacclimatized Lowlanders (22), but little is known Significance A relative fall in tissue oxygen levels (hypoxia) is a common feature of many human diseases, including heart failure, lung diseases, anemia, and many cancers, and can compromise normal cellular function. Hypoxia also occurs in healthy humans at high altitude due to low barometric pressures.…”

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confidence: 99%

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Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

165

219

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The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature. metabolism | altitude | skeletal muscle | hypoxia | mitochondria

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Section: Resultssupporting

confidence: 82%

mentioning

confidence: 99%

Metabolic basis to Sherpa altitude adaptation

Horscroft

Kotwica

Laner

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

165

219

View full text Add to dashboard Cite

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“…For the high-altitude dwellers such as Tibetans and Quechuas who have been living at Ն3,500 m for thousands of generations, the capillary density in skeletal muscle is within the normal range and the mitochondrial content of skeletal muscle is also close to that of the lowland population, yet they develop muscle fibers with smaller cross-sectional areas (29). Prolonged exposure to high-altitude hypoxia (24) or simulated hypoxia in a chamber (33) can also cause a reduction of muscle fiber size and loss of skeletal muscle mass, despite a decrease in the perfusion area per capillary (24).…”

Section: Discussionmentioning

confidence: 99%

Adaptive Myogenesis under Hypoxia

Yun

Lin

Giaccia

2005

Molecular and Cellular Biology

126

171

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Previous studies have indicated that myoblasts can differentiate and repair muscle injury after an ischemic insult. However, it is unclear how hypoxia or glucose deprivation in the ischemic microenvironment affects myoblast differentiation. We have found that myogenesis can adapt to hypoxic conditions. This adaptive mechanism is accompanied by initial inhibition of the myoD, E2A, and myogenin genes followed by resumption of their expression in an oxygen-dependent manner. The regulation of myoD transcription by hypoxia is correlated with transient deacetylation of histones associated with the myoD promoter. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1, a ubiquitous regulator of transcription under hypoxia. While myogenesis can also adapt to glucose deprivation, the combination of severe hypoxia and glucose deprivation found in an ischemic environment results in pronounced loss of myoblasts. Our studies indicate that the ischemic muscle can be repaired via the adaptive differentiation of myogenic precursors, which depends on the levels of oxygen and glucose in the ischemic microenvironment.Skeletal muscle possesses the remarkable ability to withstand chronic ischemia. However, the newly developed muscle fibers tend to be smaller in diameter than those of healthy, nonischemic myofibers (46). Interestingly, chronic exposure to high altitude can also result in smaller myofiber area and lower muscle mass in mountaineers (25). Similar myofiber differences are also observed in healthy people who live at high altitude for generations (25). Taken together, these observations suggest that decreased oxygen tension or hypoxia alone may be sufficient to alter the differentiation of myoblasts.Ischemic muscle damage is repaired by myogenic satellite cells, a small population of precursor cells located between myofibers (12,23,47). When stimulated, the otherwise quiescent satellite cells undergo terminal differentiation into myocytes to regenerate damaged myofibers. It has been found that cultured satellite cells form new muscle fibers when transplanted into ischemic muscle (12). The myogenic differentiation of myoblasts is highly orchestrated by a family of myogenic regulatory factors (MRFs), such as myoD, myogenin, myf5, and MRF4 in collaboration with the E2A gene products (E12 or E47) and/or the myogenic enhancing factors (6, 41, 53). Although a plethora of information on the embryonic development of muscle exists, there is still a lack of clear understanding of how postnatal myogenic satellite cells are regulated during muscle regeneration, especially by their microenvironment.Tissue ischemia in myocardium and skeletal muscle results in hypoxia and elevates the expression of the hypoxia-inducible transcription factor HIF-1␣ and its downstream gene, VEGF (32,40). Although ischemic tissue is exposed to hypoxia and decreased nutritional supply, cells will alter their metabolism, proliferation, and differe...

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“…The reduction in metabolic capacity might be beneficial in species that usually sustain sub-maximal rates of aerobic metabolism. Mitochondrial abundance is constitutively reduced in the muscle of Tibetan humans compared with that of native lowlanders, and is not affected by environmental O 2 availability (Kayser et al, 1991;Kayser et al, 1996). This might represent an example of genetic assimilation (Pigliucci et al, 2006), because the phenotypic plasticity exhibited by lowlanders has become constitutively expressed in Tibetans.…”

Section: Tissue O 2 Utilizationmentioning

confidence: 96%

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

Storz

Scott

Cheviron

2010

Journal of Experimental Biology

342

343

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SummaryHigh-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high-and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.

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Muscle structure and performance capacity of Himalayan Sherpas

Cited by 116 publications

References 0 publications

Metabolic basis to Sherpa altitude adaptation

Metabolic basis to Sherpa altitude adaptation

Adaptive Myogenesis under Hypoxia

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

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