Metabolic basis to Sherpa altitude adaptation.

Horscroft, James A 
Kotwica, Aleksandra O 
Laner, Verena 
West, James A 
Hennis, Philip J 

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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.

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altitude, hypoxia, metabolism, mitochondria, skeletal muscle, Adaptation, Physiological, Adult, Altitude, Atmospheric Pressure, Citric Acid Cycle, Energy Metabolism, Ethnicity, Fatty Acids, Female, Gene Frequency, Glucose, Glycolysis, Humans, Hypoxia, Male, Mitochondria, Muscle, Muscle, Skeletal, Nepal, Nitric Oxide, Oxidative Phosphorylation, Oxidative Stress, Oxygen Consumption, PPAR alpha, Polymorphism, Single Nucleotide, Tibet
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Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
Medical Research Council (MR/P011705/1)
Wellcome Trust (092738/Z/10/Z)
Medical Research Council (MR/P01836X/1)
Biotechnology and Biological Sciences Research Council (BB/F016581/1)
Medical Research Council (MC_PC_13030)
National Cancer Institute (R01CA153983)
European Commission (331756)
Wellcome Trust (214283/Z/18/Z)
The work was supported by PhD studentships from the BBSRC to JH (BB/F016581/1) and British Heart Foundation to AK (FS/09/050), an Academic Fellowship to AM from the Research Councils UK (EP/E500552/1), a Physiological Society grant and support from Oroboros Instruments. JG thanks the MRC (MC UP A90 1006) and AB Sciex. MF thanks the MRC and Faculty of Medicine, Southampton University. For full acknowledgements see SI.