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Metabolic basis to Sherpa altitude adaption

Metabolic basis to Sherpa altitude adaption
Metabolic basis to Sherpa altitude adaption
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.
0027-8424
Horscroft, James A.
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Kotwica, Aleksandra O.
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Laner, Verena
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West, James A.
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Hennis, Philip J.
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Levett, Denny Z.H.
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Howard, David J.
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Fernandez, Bernadette O.
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Burgess, Sarah L.
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Ament, Zsuzsanna
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Gilbert-Kawai, Edward T.
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Vercueil, Andre
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Mythen, Monty G.
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Branco, Cristina
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Johnson, Randall S.
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Feelisch, Martin
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Montgomery, Hugh E.
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Murray, Andrew J.
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Horscroft, James A.
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Laner, Verena
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West, James A.
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Hennis, Philip J.
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Levett, Denny Z.H.
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Howard, David J.
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Fernandez, Bernadette O.
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Burgess, Sarah L.
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Ament, Zsuzsanna
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Gilbert-Kawai, Edward T.
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Vercueil, Andre
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Mitchell, Kay
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Mythen, Monty G.
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Branco, Cristina
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Johnson, Randall S.
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Feelisch, Martin
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Montgomery, Hugh E.
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Griffin, Julian L.
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Grocott, Michael P.W.
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Gnaiger, Erich
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Martin, Daniel S.
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Murray, Andrew J.
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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, Andre, 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. and Murray, Andrew J. (2017) Metabolic basis to Sherpa altitude adaption. Proceedings of the National Academy of Sciences. (doi:10.1073/pnas.1700527114).

Record type: Article

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.

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Accepted manuscript Sherpa metabolism - Accepted Manuscript
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Accepted/In Press date: 21 April 2017
e-pub ahead of print date: 22 May 2017
Additional Information: Sherpa metabolism and altitude adaptation
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 410619
URI: https://eprints.soton.ac.uk/id/eprint/410619
ISSN: 0027-8424
PURE UUID: a3ab6af8-7525-41f2-8513-df2482d96b55
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Kay Mitchell: ORCID iD orcid.org/0000-0001-6393-8475
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158
ORCID for Michael P.W. Grocott: ORCID iD orcid.org/0000-0002-9484-7581

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Date deposited: 09 Jun 2017 09:15
Last modified: 03 Dec 2019 01:43

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Contributors

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

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