PPARα-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia
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Authors
Horscroft, James
Devaux, Jules
Strang Steel, Alice
Clark, Anna
Philp, Andrew
Harridge, Stephen
Publication Date
2019-04-01Journal Title
BBA Molecular Basis of Disease
ISSN
0925-4439
Publisher
Elsevier
Type
Article
This Version
VoR
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O'Brien, K., Horscroft, J., Devaux, J., Lindsay, R., Strang Steel, A., Clark, A., Philp, A., et al. (2019). PPARα-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia. BBA Molecular Basis of Disease https://doi.org/10.1016/j.bbadis.2018.07.027
Abstract
Hypoxia 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 (PPARα), a master regulator of fat metabolism.
Here we investigated whether nitrate supplementation protects skeletal
muscle mitochondrial function in hypoxia and whether PPARα is required
for this effect. Wild-type and PPARα knockout (PPARα-/-) 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 PPARα. 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
PPARα-/- mice. Our results support the notion that nitrate
supplementation can aid hypoxia tolerance and indicate that nitrate can
exert effects independently of PPARα.
Keywords
muscle, metabolism, hypoxia, nitric oxide, fatty acids
Relationships
Is supplemented by: https://doi.org/10.17863/CAM.25657
Sponsorship
This work was supported by King’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].
Funder references
Biotechnology and Biological Sciences Research Council (BB/F016581/1)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.bbadis.2018.07.027
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287730
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