Impaired myogenesis in estrogen-related receptor γ (ERRγ)-deficient skeletal myocytes due to oxidative stress

Specialized contractile function and increased mitochondrial number and oxidative capacity are hallmark features of myocyte differentiation. The estrogen-related receptors (ERRs) can regulate mitochondrial biogenesis or mitochondrial enzyme expression in skeletal muscle, suggesting that ERRs may have a role in promoting myogenesis. Therefore, we characterized myogenic programs in primary myocytes isolated from wild-type (M-ERR gamma WT) and muscle-specific ERR gamma(-/-) (M-ERR gamma(-/-)) mice. Myotube maturation and number were decreased throughout differentiation in M-ERR gamma(-/-) primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M-ERR gamma WT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M-ERR gamma(-/-) myotubes, while medium-chain fatty acid oxidation was increased by 34% in M-ERR gamma(-/-) myoblasts and 36% in M-ERR gamma(-/-) myotubes. Concomitant with increased reliance on mitochondrial beta-oxidation, H2O2 production was significantly increased by 40% in M-ERR gamma(-/-) myoblasts and 70% in M-ERR gamma(-/-) myotubes compared to M-ERR gamma WT myocytes. ROS activation of FoxO and NF-kappa B and their downstream targets, atrogin-1 and MuRF1, was observed in M-ERR gamma(-/-) myocytes. The antioxidant N-acetyl cysteine rescued myotube formation and atrophy gene induction in M-ERR gamma(-/-) myocytes. These results suggest that loss of ERR gamma causes metabolic defects and oxidative stress that impair myotube formation through activation of skeletal muscle atrophy pathways.-Murray, J., Auwerx, J., Huss, J. M. Impaired myogenesis in estrogen-related receptor gamma (ERR gamma)-deficient skeletal myocytes due to oxidative stress. FASEB J. 27, 135-150 (2013). www.fasebj.org