Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming

Matsakas, Antonios; Yadav, Vikas; Lorca, Sabina; Narkar, Vihang

Abstract

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 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 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.

Citation

Matsakas, A., Yadav, V., Lorca, S., & Narkar, V. (2013). Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming. FASEB Journal, 27(10), 4004-4016. https://doi.org/10.1096/fj.13-228296

• Journal Article Type: Article
• Acceptance Date: Jun 4, 2013
• Online Publication Date: Jun 18, 2013
• Publication Date: 2013-10
• Deposit Date: Nov 13, 2014
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• Print ISSN: 0892-6638
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 10
• Pages: 4004-4016
• DOI: https://doi.org/10.1096/fj.13-228296
• Keywords: estrogen-related receptors, fiber type, nuclear receptors, muscle degenerative diseases.,
• Public URL: https://hull-repository.worktribe.com/output/470170
• Contract Date: Nov 13, 2014