Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Accessibility Statement
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Special Feature Articles - Most Recent
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • List of Issues
  • Front Matter
  • News
    • For the Press
    • This Week In PNAS
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Editorial and Journal Policies
    • Submission Procedures
    • Fees and Licenses

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology
Research Article

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, View ORCID ProfileKay Mitchell, Monty G. Mythen, Cristina Branco, View ORCID ProfileRandall S. Johnson, Martin Feelisch, Hugh E. Montgomery, Julian L. Griffin, Michael P. W. Grocott, Erich Gnaiger, Daniel S. Martin, and Andrew J. Murray
PNAS June 13, 2017 114 (24) 6382-6387; first published May 22, 2017; https://doi.org/10.1073/pnas.1700527114
James A. Horscroft
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aleksandra O. Kotwica
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Verena Laner
bOroboros Instruments, A-6020 Innsbruck, Austria;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
James A. West
cDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
dMedical Research Council Human Nutrition Research Unit, University of Cambridge, Cambridge CB1 9NL, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Philip J. Hennis
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Denny Z. H. Levett
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David J. Howard
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bernadette O. Fernandez
fFaculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah L. Burgess
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zsuzsanna Ament
cDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
dMedical Research Council Human Nutrition Research Unit, University of Cambridge, Cambridge CB1 9NL, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edward T. Gilbert-Kawai
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
André Vercueil
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Blaine D. Landis
gJudge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kay Mitchell
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kay Mitchell
Monty G. Mythen
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cristina Branco
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Randall S. Johnson
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Randall S. Johnson
Martin Feelisch
fFaculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
hNIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hugh E. Montgomery
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julian L. Griffin
cDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;
dMedical Research Council Human Nutrition Research Unit, University of Cambridge, Cambridge CB1 9NL, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael P. W. Grocott
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
fFaculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom;
hNIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 6YD, United Kingdom;
iCentre for Human Integrative Physiology, University of Southampton, Southampton SO16 6YD, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Erich Gnaiger
bOroboros Instruments, A-6020 Innsbruck, Austria;
jDepartment of General and Transplant Surgery, Medical University of Innsbruck, A-6020 Innsbruck, Austria
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel S. Martin
eUniversity College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NHS Foundation Trust National Institute for Health Research (NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, University College London, London W1T 7HA, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Andrew J. Murray
aDepartment of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, United Kingdom;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ajm267@cam.ac.uk
  1. Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 21, 2017 (received for review January 10, 2017)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

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.

  • metabolism
  • altitude
  • skeletal muscle
  • hypoxia
  • mitochondria

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.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Metabolic basis to Sherpa altitude adaptation
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Sherpa metabolism and 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
Proceedings of the National Academy of Sciences Jun 2017, 114 (24) 6382-6387; DOI: 10.1073/pnas.1700527114

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Sherpa metabolism and 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
Proceedings of the National Academy of Sciences Jun 2017, 114 (24) 6382-6387; DOI: 10.1073/pnas.1700527114
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 114 (24)
Table of Contents

Submit

Sign up for Article Alerts

Article Classifications

  • Biological Sciences
  • Physiology

Jump to section

  • Article
    • Abstract
    • Results and Discussion
    • Conclusions
    • Materials and Methods
    • SI Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

Abstract depiction of a guitar and musical note
Science & Culture: At the nexus of music and medicine, some see disease treatments
Although the evidence is still limited, a growing body of research suggests music may have beneficial effects for diseases such as Parkinson’s.
Image credit: Shutterstock/agsandrew.
Scientist looking at an electronic tablet
Opinion: Standardizing gene product nomenclature—a call to action
Biomedical communities and journals need to standardize nomenclature of gene products to enhance accuracy in scientific and public communication.
Image credit: Shutterstock/greenbutterfly.
One red and one yellow modeled protein structures
Journal Club: Study reveals evolutionary origins of fold-switching protein
Shapeshifting designs could have wide-ranging pharmaceutical and biomedical applications in coming years.
Image credit: Acacia Dishman/Medical College of Wisconsin.
White and blue bird
Hazards of ozone pollution to birds
Amanda Rodewald, Ivan Rudik, and Catherine Kling talk about the hazards of ozone pollution to birds.
Listen
Past PodcastsSubscribe
Goats standing in a pin
Transplantation of sperm-producing stem cells
CRISPR-Cas9 gene editing can improve the effectiveness of spermatogonial stem cell transplantation in mice and livestock, a study finds.
Image credit: Jon M. Oatley.

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Latest Articles
  • Archive

PNAS Portals

  • Anthropology
  • Chemistry
  • Classics
  • Front Matter
  • Physics
  • Sustainability Science
  • Teaching Resources

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Librarians
  • Press
  • Site Map
  • PNAS Updates

Feedback    Privacy/Legal

Copyright © 2021 National Academy of Sciences. Online ISSN 1091-6490