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Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications.

Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications.
Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications.
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 selection of variants in PPARA, encoding peroxisome proliferator-activated receptor α (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.
0300-5127
599-607
Murray, Andrew J.
cec08ce8-91ec-42c6-9746-c4a0d9306e7b
Montgomery, Hugh
ec760637-aea7-43be-98d1-71a1f72e6efa
Grocott, Michael
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Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Martin, Daniel S.
3e441b48-9221-4308-8ae6-49cbde20753f
Murray, Andrew J.
cec08ce8-91ec-42c6-9746-c4a0d9306e7b
Montgomery, Hugh
ec760637-aea7-43be-98d1-71a1f72e6efa
Grocott, Michael
1e87b741-513e-4a22-be13-0f7bb344e8c2
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Martin, Daniel S.
3e441b48-9221-4308-8ae6-49cbde20753f

Murray, Andrew J., Montgomery, Hugh, Grocott, Michael, Feelisch, Martin and Martin, Daniel S. (2018) Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications. Biochemical Society Transactions, 46 (3), 599-607. (doi:10.1042/BST20170502).

Record type: Article

Abstract

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 selection of variants in PPARA, encoding peroxisome proliferator-activated receptor α (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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Accepted/In Press date: 27 March 2018
e-pub ahead of print date: 20 April 2018

Identifiers

Local EPrints ID: 420081
URI: http://eprints.soton.ac.uk/id/eprint/420081
ISSN: 0300-5127
PURE UUID: 8c9407e8-da4b-4951-b582-0d118fa60f3c
ORCID for Michael Grocott: ORCID iD orcid.org/0000-0002-9484-7581
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 26 Apr 2018 16:30
Last modified: 22 Nov 2021 06:20

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Contributors

Author: Andrew J. Murray
Author: Hugh Montgomery
Author: Michael Grocott ORCID iD
Author: Martin Feelisch ORCID iD
Author: Daniel S. Martin

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