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Metabolic basis to Sherpa altitude adaptation.

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cam.issuedOnline2017-05-22
cam.orpheus.successThu Jan 30 12:53:56 GMT 2020 - Embargo updated
dc.contributor.authorHorscroft, James A
dc.contributor.authorKotwica, Aleksandra O
dc.contributor.authorLaner, Verena
dc.contributor.authorWest, James A
dc.contributor.authorHennis, Philip J
dc.contributor.authorLevett, Denny ZH
dc.contributor.authorHoward, David J
dc.contributor.authorFernandez, Bernadette O
dc.contributor.authorBurgess, Sarah L
dc.contributor.authorAment, Zsuzsanna
dc.contributor.authorGilbert-Kawai, Edward T
dc.contributor.authorVercueil, André
dc.contributor.authorLandis, Blaine D
dc.contributor.authorMitchell, Kay
dc.contributor.authorMythen, Monty G
dc.contributor.authorBranco, Cristina
dc.contributor.authorJohnson, Randall S
dc.contributor.authorFeelisch, Martin
dc.contributor.authorMontgomery, Hugh E
dc.contributor.authorGriffin, Julian L
dc.contributor.authorGrocott, Michael PW
dc.contributor.authorGnaiger, Erich
dc.contributor.authorMartin, Daniel S
dc.contributor.authorMurray, Andrew J
dc.contributor.orcidMitchell, Kay [0000-0001-6393-8475]
dc.contributor.orcidJohnson, Randall S [0000-0002-4084-6639]
dc.date.accessioned2017-05-16T15:12:07Z
dc.date.available2017-05-16T15:12:07Z
dc.date.issued2017-06-13
dc.description.abstractThe 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.
dc.description.sponsorshipThe 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.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.9676
dc.identifier.eissn1091-6490
dc.identifier.issn0027-8424
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264269
dc.languageeng
dc.language.isoeng
dc.publisherProceedings of the National Academy of Sciences
dc.publisher.urlhttp://dx.doi.org/10.1073/pnas.1700527114
dc.subjectaltitude
dc.subjecthypoxia
dc.subjectmetabolism
dc.subjectmitochondria
dc.subjectskeletal muscle
dc.subjectAdaptation, Physiological
dc.subjectAdult
dc.subjectAltitude
dc.subjectAtmospheric Pressure
dc.subjectCitric Acid Cycle
dc.subjectEnergy Metabolism
dc.subjectEthnicity
dc.subjectFatty Acids
dc.subjectFemale
dc.subjectGene Frequency
dc.subjectGlucose
dc.subjectGlycolysis
dc.subjectHumans
dc.subjectHypoxia
dc.subjectMale
dc.subjectMitochondria, Muscle
dc.subjectMuscle, Skeletal
dc.subjectNepal
dc.subjectNitric Oxide
dc.subjectOxidative Phosphorylation
dc.subjectOxidative Stress
dc.subjectOxygen Consumption
dc.subjectPPAR alpha
dc.subjectPolymorphism, Single Nucleotide
dc.subjectTibet
dc.titleMetabolic basis to Sherpa altitude adaptation.
dc.typeArticle
dcterms.dateAccepted2017-04-21
prism.endingPage6387
prism.publicationDate2017
prism.publicationNameProc Natl Acad Sci U S A
prism.startingPage6382
prism.volume114
pubs.funder-project-idMedical Research Council (MR/P011705/1)
pubs.funder-project-idWellcome Trust (092738/Z/10/Z)
pubs.funder-project-idMedical Research Council (MR/P01836X/1)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/F016581/1)
pubs.funder-project-idMedical Research Council (MC_PC_13030)
pubs.funder-project-idNational Cancer Institute (R01CA153983)
pubs.funder-project-idEuropean Commission (331756)
pubs.funder-project-idWellcome Trust (214283/Z/18/Z)
rioxxterms.licenseref.startdate2017-06
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1073/pnas.1700527114

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