title: RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice.
abstract: Heterotopic ossification (HO) and fatty infiltration (FI) often occur in diseased skeletal muscle and have been previously described in various animal models of Duchenne muscular dystrophy (DMD); however, the pathological mechanisms remain largely unknown. Dystrophin-deficient mdx mice and dystrophin/utrophin double-knockout (dKO) mice are mouse models of DMD; however, mdx mice display a strong muscle regeneration capacity, while dKO mice exhibit a much more severe phenotype, which is similar to patients with DMD. Our results revealed that more extensive HO, but not FI, occurred in the skeletal muscle of dKO mice versus mdx mice, and RhoA activation specifically occurred at the sites of HO. Moreover, the gene expression of RhoA, BMPs, and several inflammatory factors were significantly up-regulated in muscle stem cells isolated from dKO mice; while inactivation of RhoA in the cells with RhoA/ROCK inhibitor Y-27632 led to reduced osteogenic potential and improved myogenic potential. Finally, inactivation of RhoA signaling in the dKO mice with Y-27632 improved muscle regeneration and reduced the expression of BMPs, inflammation, HO, and intramyocellular lipid accumulation in both skeletal and cardiac muscle. Our results revealed that RhoA represents a major molecular switch in the regulation of HO and muscle regeneration in dystrophic skeletal muscle of mice.
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh, 450 Technology Dr., Pittsburgh, PA 15219, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Mu
authors.forename: Arvydas
authors.initials: A
authors.lastname: Usas
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Kurt
authors.initials: K
authors.lastname: Weiss
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism; D009999:Ossification, Heterotopic / Q000235:genetics / Q000378:metabolism; D049411:Utrophin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D001578:Benzopyrans; D016189:Dystrophin; D049411:Utrophin; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C074338:Y 26763
keywords: ROCK; intramyocellular lipid accumulation; mdx; utrophin-/-