Journal
FASEB JOURNAL
Volume 27, Issue 10, Pages 4004-4016Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-228296
Keywords
estrogen-related receptors; fiber type; nuclear receptors; muscle degenerative diseases
Categories
Funding
- University of Texas Medical School at Houston intramural funds
- Muscular Dystrophy Association [MDA 174408]
- American Heart Association [AHA 11SDG7600213]
- American Diabetes Association [ADA 1-13-BS-127]
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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.
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