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‐ERRγWT) and muscle‐specific ERRγ–/– (M‐ERRγ–/–) mice. Myotube maturation and number were decreased throughout differentiation in M‐ERRγ–/– primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M‐ERRγWT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M‐ERRγ–/– myotubes, while medium‐chain fatty acid oxidation was increased by 34% in M‐ERRγ–/– myoblasts and 36% in M‐ERRγ–/– myotubes. Concomitant with increased reliance on mitochondrial β‐oxidation, H2O2 production was significantly increased by 40% in M‐ERRγ–/– myoblasts and 70% in M‐ERRγ–/– myotubes compared to M‐ERRγWT myocytes. ROS activation of FoxO and NF‐κB and their downstream targets, atrogin‐1 and MuRF1, was observed in M‐ERRγ–/– myocytes. The antioxidant N‐acetyl cysteine rescued myotube formation and atrophy gene induction in M‐ERRγ–/– myocytes. These results suggest that loss of ERRγ 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 γ (ERRγ)‐deficient skeletal myocytes due to oxidative stress. FASEB J. 27, 135–150 (2013). www.fasebj.org