title: Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming.
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.
authors.affiliation: 1Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine, University of Texas Medical School at Houston, IMM/SRB 430F, 1825 Pressler St., Houston, TX 77030, USA. vihang.a.narkar@uth.tmc.edu.
authors.forename: Antonios
authors.initials: A
authors.lastname: Matsakas
authors.forename: Vikas
authors.initials: V
authors.lastname: Yadav
authors.forename: Sabina
authors.initials: S
authors.lastname: Lorca
authors.forename: Vihang
authors.initials: V
authors.lastname: Narkar
mesh_terms: D000818:Animals; D003402:Creatine Kinase; D049028:Dystrophin-Associated Protein Complex / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D049411:Utrophin / Q000235:genetics / Q000378:metabolism
chemical_list: D049028:Dystrophin-Associated Protein Complex; C490916:Esrrg protein, mouse; D011960:Receptors, Estrogen; D049411:Utrophin; D003402:Creatine Kinase
keywords: estrogen-related receptors; fiber type; muscle degenerative diseases; nuclear receptors