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PPARĪ±-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia

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cam.issuedOnline2018-07-25
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.25657
dc.contributor.authorO'Brien, Katie
dc.contributor.authorHorscroft, James
dc.contributor.authorDevaux, Jules
dc.contributor.authorLindsay, Ross
dc.contributor.authorStrang Steel, Alice
dc.contributor.authorClark, Anna
dc.contributor.authorPhilp, Andrew
dc.contributor.authorHarridge, Stephen
dc.contributor.authorMurray, AJ
dc.contributor.orcidO'Brien, Katie [0000-0002-0189-1971]
dc.contributor.orcidLindsay, Ross [0000-0001-7760-613X]
dc.contributor.orcidMurray, Andrew [0000-0002-0929-9315]
dc.date.accessioned2019-01-09T14:22:28Z
dc.date.available2019-01-09T14:22:28Z
dc.date.issued2019-04-01
dc.description.abstractHypoxia is a feature of many disease states where convective oxygen delivery is impaired, and is known to suppress oxidative metabolism. Acclimation to hypoxia thus requires metabolic remodelling, however hypoxia tolerance may be aided by dietary nitrate supplementation. Nitrate improves tissue oxygenation and has been shown to modulate skeletal muscle tissue metabolism via transcriptional changes, including through the activation of peroxisome proliferator- activated receptor alpha (PPARĪ±), a master regulator of fat metabolism. Here we investigated whether nitrate supplementation protects skeletal muscle mitochondrial function in hypoxia and whether PPARĪ± is required for this effect. Wild-type and PPARĪ± knockout (PPARĪ±-/-) mice were supplemented with sodium nitrate via the drinking water or sodium chloride as control, and exposed to environmental hypoxia (10% O2) or normoxia for 4 weeks. Hypoxia suppressed mitochondrial respiratory function in mouse soleus, an effect partially alleviated through nitrate supplementation, but occurring independently of PPARĪ±. Specifically, hypoxia resulted in 26% lower mass specific fatty acid-supported LEAK respiration and 23% lower pyruvate-supported oxidative phosphorylation capacity. Hypoxia also resulted in 24% lower citrate synthase activity in mouse soleus, possibly indicating a loss of mitochondrial content. These changes were not seen, however, in hypoxic mice when supplemented with dietary nitrate, indicating a nitrate dependent preservation of mitochondrial function. Moreover, this was observed in both wild-type and PPARĪ±-/- mice. Our results support the notion that nitrate supplementation can aid hypoxia tolerance and indicate that nitrate can exert effects independently of PPARĪ±.
dc.description.sponsorshipThis work was supported by Kingā€™s College London, the Biotechnology and Biological Sciences Research Councils [grant number: BB/F016581/1] and the Research Councils UK [grant number: EP/E500552/1].
dc.identifier.doi10.17863/CAM.35045
dc.identifier.eissn1879-260X
dc.identifier.issn0925-4439
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287730
dc.language.isoeng
dc.publisherElsevier
dc.publisher.urlhttps://www.sciencedirect.com/science/article/pii/S092544391830276X?via=ihub
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectmuscle
dc.subjectmetabolism
dc.subjecthypoxia
dc.subjectnitric oxide
dc.subjectfatty acids
dc.titlePPARĪ±-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia
dc.typeArticle
dcterms.dateAccepted2018-07-20
prism.publicationNameBBA Molecular Basis of Disease
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/F016581/1)
rioxxterms.licenseref.startdate2018-07-20
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.bbadis.2018.07.027

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