Impaired myogenesis in estrogen-related receptor ? (ERR?)-deficient skeletal myocytes due to oxidative stress.

ABSTRACT: 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?WT) and muscle-specific ERR?(-/-) (M-ERR?(-/-)) mice. Myotube maturation and number were decreased throughout differentiation in M-ERR?(-/-) primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M-ERR?WT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M-ERR?(-/-) myotubes, while medium-chain fatty acid oxidation was increased by 34% in M-ERR?(-/-) myoblasts and 36% in M-ERR?(-/-) myotubes. Concomitant with increased reliance on mitochondrial ?-oxidation, H(2)O(2) production was significantly increased by 40% in M-ERR?(-/-) myoblasts and 70% in M-ERR?(-/-) myotubes compared to M-ERR?WT myocytes. ROS activation of FoxO and NF-?B and their downstream targets, atrogin-1 and MuRF1, was observed in M-ERR?(-/-) myocytes. The antioxidant N-acetyl cysteine rescued myotube formation and atrophy gene induction in M-ERR?(-/-) myocytes. These results suggest that loss of ERR? causes metabolic defects and oxidative stress that impair myotube formation through activation of skeletal muscle atrophy pathways.

SUBMITTER: Murray J 

PROVIDER: S-EPMC3528312 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature