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.