Metabolic basis to Sherpa altitude adaptation

James A. Horscroft; Aleksandra O. Kotwica; Verena Laner; James A. West; Philip J. Hennis; Denny Z. H. Levett; David J. Howard; Bernadette O. Fernandez; Sarah L. Burgess; Zsuzsanna Ament; Edward T. Gilbert-Kawai; André Vercueil; Blaine D. Landis; Kay Mitchell; Monty G. Mythen; Cristina Branco; Randall S. Johnson; Martin Feelisch; Hugh E. Montgomery; Julian L. Griffin; Michael P. W. Grocott; Erich Gnaiger; Daniel S. Martin; Andrew J. Murray

doi:10.1073/pnas.1700527114

Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 21, 2017 (received for review January 10, 2017)

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. Human populations resident at high altitude in the Himalayas have evolved mechanisms that allow them to survive and perform, including adaptations that preserve oxygen delivery to the tissues. Here, we studied one such population, the Sherpas, and found metabolic adaptations, underpinned by genetic differences, that allow their tissues to use oxygen more efficiently, thereby conserving muscle energy levels at high altitude, and possibly contributing to the superior performance of elite climbing Sherpas at extreme altitudes.

Abstract

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.

Footnotes

↵¹To whom correspondence should be addressed. Email: ajm267{at}cam.ac.uk.

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.
Conflict of interest statement: E.G. is Chief Executive Officer and V.L. is Chief Operating Officer of Oroboros Instruments.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700527114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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