Effect of hypoxia exposure on the recovery of skeletal muscle phenotype during regeneration

Abstract

Hypoxia impairs the muscle fibre-type shift from fast-to-slow during post-natal development; however, this adaptation could be a consequence of the reduced voluntary physical activity associated with hypoxia exposure rather than the result of hypoxia per se. Moreover, muscle oxidative capacity could be reduced in hypoxia, particularly when hypoxia is combined with additional stress. Here, we used a model of muscle regeneration to mimic the fast-to-slow fibre-type conversion observed during post-natal development. We hypothesised that hypoxia would impair the recovery of the myosin heavy chain (MHC) profile and oxidative capacity during muscle regeneration. To test this hypothesis, the soleus muscle of female rats was injured by notexin and allowed to recover for 3, 7, 14 and 28 days under normoxia or hypobaric hypoxia (5,500 m altitude) conditions. Ambient hypoxia did not impair the recovery of the slow MHC profile during muscle regeneration. However, hypoxia moderately decreased the oxidative capacity (assessed from the activity of citrate synthase) of intact muscle and delayed its recovery in regenerated muscle. Hypoxia transiently increased in both regenerated and intact muscles the content of phosphorylated AMPK and Pgc-1α mRNA, two regulators involved in mitochondrial biogenesis, while it transiently increased in intact muscle the mRNA level of the mitophagic factor BNIP3. In conclusion, hypoxia does not act to impair the fast-to-slow MHC isoform transition during regeneration. Hypoxia alters the oxidative capacity of intact muscle and delays its recovery in regenerated muscle; however, this adaptation to hypoxia was independent of the studied regulators of mitochondrial turn-over.

Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity

“…Our results revealed that hypoxia delayed the formation and growth of new myofibers during the first week after injury, but did not affect the final recovery of muscle mass and the fiber cross‐sectional area after 4 wk (45). Our results also indicate that hypoxia delays the recovery of the oxidative capacity of regenerated muscle without affecting the maturation of its contractile phenotype (i.e., the transition from fast to slow MHC isoforms observed during muscle regeneration) (7). Similarly, it was demonstrated that the formation of myotubes, which was repressed during the early phase of differentiation at low O 2 level (0.5% O 2 ) in vitro , was able to progress during the late phase (12 d ) (41).…”

“…9 for a recent review). In our recent studies, we did not observe any signs of regeneration in skeletal muscles (control soleus and plantaris muscles) from rats exposed to severe hypobaric hypoxia (7, 8, 13, 45), suggesting that hypoxia per se does not trigger muscle regeneration in animals.…”

“…Chronic exposure to severe hypoxia has been shown to induce skeletal muscle adaptations, including metabolic changes (e.g., reduced oxidative capacity) (7, 8) and muscle atrophy [see Favier et al . (9) for a recent review].…”

“…Chronic exposure to severe hypoxia has been shown to induce skeletal muscle adaptations, including metabolic changes (e.g., reduced oxidative capacity) (7,8) and muscle atrophy [see Favier et al (9) for a recent review]. In particular, a loss of skeletal muscle mass (i.e., muscle atrophy) has been observed in humans (10) and in rodents (11)(12)(13) in response to severe ambient hypoxia.…”

Application of recombinant peroxisome proliferator-activated receptor-γ coactivator-1α mediates neovascularization in the retina

“…In particular, PGC-1α regulates oxidative phosphorylation, mitochondrial biogenesis and respiration (22,23). Numerous previous studies have suggested that ischemia and hypoxia significantly induce the expression of PGC-1α (5)(6)(7)(8)(9)(10)(11)24,25). Arany et al (12) reported that PGC-1α was able to upregulate the expression of angiogenic factors such as VEGF, and promote the formation of new blood vessels in skeletal muscle.…”