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Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming
Author(s) -
Matsakas Antonios,
Yadav Vikas,
Lorca Sabina,
Narkar Vihang
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-228296
Subject(s) - duchenne muscular dystrophy , dystrophin , muscular dystrophy , itga7 , skeletal muscle , mdx mouse , endocrinology , myocyte , medicine , biology
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‐γ (ERRγ), and its metabolic and angiogenic targets are downregulated (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 ERRγ selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERRγ enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33–66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERRγ pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERRγ did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERRγ. In summary, ERRγ‐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 ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming. FASEB J. 27, 4004–4016 (2013). www.fasebj.org