Abstract
Extremely reduced oxygen (O2) levels are detrimental to myogenic differentiation and multinucleated myotube formation, and chronic exposure to high-altitude hypoxia has been reported to be an important factor in skeletal muscle atrophy. However, how chronic hypoxia causes muscle dysfunction remains unknown. In the present study, we found that severe hypoxia (1% O2) significantly inhibited the function of C2C12 cells (from a myoblast cell line). Importantly, the impairment was continuously manifested even during culture under normoxic conditions for several passages. Mechanistically, we revealed that histone deacetylases 9 (HDAC9), a member of the histone deacetylase family, was significantly increased in C2C12 cells under hypoxic conditions, thereby inhibiting intracellular autophagy levels by directly binding to the promoter regions of Atg7, Beclin1, and LC3. This phenomenon resulted in the sequential dephosphorylation of GSK3β and inactivation of the canonical Wnt pathway, impairing the function of the C2C12 cells. Taken together, our results suggest that hypoxia-induced myoblast dysfunction is due to aberrant epigenetic regulation of autophagy, and our experimental evidence reveals the possible molecular pathogenesis responsible for some muscle diseases caused by chronic hypoxia and suggests a potential therapeutic option.
Highlights
Chronic high-altitude hypoxia contributes to the muscle atrophy observed in patients with pathologies associated with a hypoxic microenvironment, such as chronic obstructive pulmonary disease (COPD) and arteriosclerosis obliterans[1]
To investigate the effect of hypoxia on the function of myoblasts, the C2C12 cells were exposed to hypoxia (1% O2) or were maintained under standard conditions (21% O2)
The viability and proliferation of the C2C12 were significantly reduced in the hypoxia group compared with the control groups, as shown by MTT and Edu analyses (Fig. 1b, c), indicating that hypoxia promoted the viability of the C2C12 initially, the proliferation capacity was reduced after 7 days of exposure to hypoxia
Summary
Chronic high-altitude hypoxia contributes to the muscle atrophy observed in patients with pathologies associated with a hypoxic microenvironment, such as chronic obstructive pulmonary disease (COPD) and arteriosclerosis obliterans[1]. Some studies have reported that the hypoxia-induced inhibitory effect on muscle regeneration is a temporary and reversible process[2], which seems to delay myogenic differentiation. Myoblasts are required for this process because, by successfully differentiating and fusing with each other, they regenerate the characteristic multinucleated myofibers; they play an important role in maintaining muscle structure and mass[5]. Some studies have shown that 1% O2 represses the myogenic differentiation of C2C12 (from a myoblast cell line)[2,6], whereas a 3–6% O2 level can promote myogenesis[7]. Previous studies have reported that severe hypoxia negatively regulates myogenic differentiation by inhibiting MyoD or Myogenin in myoblasts in a manner that is dependent on[3] or independent of[6,8] hypoxia-inducible factor (HIF1α), a major contributor to the response to hypoxia signaling
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