Muscle ERR gamma mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming

作者：Matsakas Antonios; Yadav Vikas; Lorca Sabina; Narkar Vihang^*

来源：The FASEB Journal, 2013, 27(10): 4004-4016.

DOI：10.1096/fj.13-228296

• estrogen-related receptors
• fiber type
• nuclear receptors
• muscle degenerative diseases

Treatment of Duchenne muscular dystrophy (DMD) by replacing mutant dystrophin or restoring dystrophin-associated glycoprotein complex (DAG) has been clinically challenging. Instead, identifying and targeting muscle pathways deregulated in DMD will provide new therapeutic avenues. We report that the expression of nuclear receptor estrogen-related receptor- (ERR), and its metabolic and angiogenic targets are down-regulated (50-85%) in skeletal muscles of mdx mice (DMD model) vs. wild-type mice. Corelatively, oxidative myofibers, muscle vasculature, and exercise tolerance (33%) are decreased in mdx vs. wild-type mice. Overexpressing ERR selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERR enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33-66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERR pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERR did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERR. In summary, ERR-dependent metabolic and angiogenic gene program is defective in DMD, and we demonstrate that its restoration is a potential strategy for treating muscular dystrophy.Matsakas, A., Yadav, V., Lorca, S., Narkar, V. Muscle ERR mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming.

• 出版日期2013-10