Metabolic basis to Sherpa altitude adaptation

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 24; pp. 6382 - 6387
Main Authors:	Horscroft, James A., Kotwica, Aleksandra O., Laner, Verena, West, James A., Hennis, Philip J., Levett, Denny Z. H., Howard, David J., Fernandez, Bernadette O., Burgess, Sarah L., Ament, Zsuzsanna, Gilbert-Kawai, Edward T., Vercueil, André, Landis, Blaine D., Mitchell, Kay, Mythen, Monty G., Branco, Cristina, Johnson, Randall S., Feelisch, Martin, Montgomery, Hugh E., Griffin, Julian L., Grocott, Michael P. W., Gnaiger, Erich, Martin, Daniel S., Murray, Andrew J.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 13-06-2017
Series:	From the Cover
Subjects:	Adaptation Adaptation, Physiological - genetics Adult Altitude Ascent Atmospheric Pressure Biological Sciences Citric Acid Cycle Energy Metabolism Ethnic Groups - genetics Fatty acids Fatty Acids - metabolism Female Gene Frequency Glucose - metabolism Glycolysis High altitude Human populations Humans Hypoxia Hypoxia - genetics Hypoxia - metabolism Hypoxia - physiopathology Male Medicin och hälsovetenskap Metabolism Minority & ethnic groups Mitochondria, Muscle - metabolism Muscle, Skeletal - metabolism Nepal Nitric Oxide - blood Oxidation Oxidative Phosphorylation Oxidative Stress Oxygen Oxygen Consumption Polymorphism, Single Nucleotide PPAR alpha - genetics PPAR alpha - metabolism Skeletal muscle Tibet - ethnology Himalaya Mountains altitude hypoxia metabolism skeletal muscle mitochondria
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: J.A.H., A.O.K., D.Z.H.L., E.T.G.-K., K.M., M.G.M., M.F., H.E.M., J.L.G., M.P.W.G., E.G., D.S.M., and A.J.M. designed research; J.A.H., A.O.K., V.L., J.A.W., P.J.H., D.Z.H.L., D.J.H., B.O.F., S.L.B., Z.A., E.T.G.-K., A.V., K.M., C.B., R.S.J., M.F., J.L.G., M.P.W.G., E.G., D.S.M., and A.J.M. performed research; J.A.W., J.L.G., and E.G. contributed new reagents/analytic tools; J.A.H., A.O.K., V.L., J.A.W., P.J.H., B.O.F., S.L.B., B.D.L., J.L.G., E.G., and A.J.M. analyzed data; and J.A.H., M.F., H.E.M., J.L.G., M.P.W.G., E.G., D.S.M., and A.J.M. wrote the paper. Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 21, 2017 (received for review January 10, 2017)
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.1700527114