Ascent to high altitude is associated with physiological responses that counter the stress of hypobaric hypoxia by increasing oxygen delivery and by altering tissue oxygen utilisation via metabolic modulation. At the cellular level, the transcriptional response to hypoxia is mediated by the hypoxia-inducible factor (HIF) pathway and results in promotion of glycolytic capacity and suppression of oxidative metabolism. In Tibetan highlanders, gene variants encoding components of the HIF pathway have undergone selection and are associated with adaptive phenotypic changes, including suppression of erythropoiesis and increased blood lactate levels. In some highland populations, there has also been a selection of variants in PPARA, encoding peroxisome proliferator-activated receptor alpha (PPARα), a transcriptional regulator of fatty acid metabolism. In one such population, the Sherpas, lower muscle PPARA expression is associated with a decreased capacity for fatty acid oxidation, potentially improving the efficiency of oxygen utilisation. In lowlanders ascending to altitude, a similar suppression of fatty acid oxidation occurs, although the underlying molecular mechanism appears to differ along with the consequences. Unlike lowlanders, Sherpas appear to be protected against oxidative stress and the accumulation of intramuscular lipid intermediates at altitude. Moreover, Sherpas are able to defend muscle ATP and phosphocreatine levels in the face of decreased oxygen delivery, possibly due to suppression of ATP demand pathways. The molecular mechanisms allowing Sherpas to successfully live, work and reproduce at altitude may hold the key to novel therapeutic strategies for the treatment of diseases to which hypoxia is a fundamental contributor.
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June 2018
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The structure of a Nucleosome, in which DNA is wrapped around a histone core. In this issue of Biochemical Society Transactions, Taniguchi et al. review recent advances in exploring Nucleosome-level 3D organization of the genome; for details see pages 491–501.
Review Article|
April 20 2018
Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications
Andrew J. Murray;
1Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, U.K.
Correspondence: Andrew Murray (ajm267@cam.ac.uk)
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Hugh E. Montgomery;
Hugh E. Montgomery
2University College London Centre for Altitude Space and Extreme Environment Medicine, UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, London, U.K.
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Martin Feelisch;
Martin Feelisch
3Faculty of Medicine (CES) and Institute for Life Science, University of Southampton, Southampton, U.K.
4 NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, U.K.
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Michael P.W. Grocott;
Michael P.W. Grocott
3Faculty of Medicine (CES) and Institute for Life Science, University of Southampton, Southampton, U.K.
4 NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, U.K.
5Centre for Human Integrative Physiology, Faculty of Medicine, University of Southampton, Southampton, U.K.
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Daniel S. Martin
Daniel S. Martin
2University College London Centre for Altitude Space and Extreme Environment Medicine, UCLH NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, London, U.K.
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Publisher: Portland Press Ltd
Received:
February 09 2018
Revision Received:
March 24 2018
Accepted:
March 27 2018
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem Soc Trans (2018) 46 (3): 599–607.
Article history
Received:
February 09 2018
Revision Received:
March 24 2018
Accepted:
March 27 2018
Citation
Andrew J. Murray, Hugh E. Montgomery, Martin Feelisch, Michael P.W. Grocott, Daniel S. Martin; Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications. Biochem Soc Trans 19 June 2018; 46 (3): 599–607. doi: https://doi.org/10.1042/BST20170502
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