RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice.

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.
AuthorsXiaodong Mu, Arvydas Usas, Ying Tang, Aiping Lu, Bing Wang, Kurt Weiss, Johnny Huard
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 9 Pg. 3619-31 (Sep 2013) ISSN: 1530-6860 [Electronic] United States
PMID23704088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzopyrans
  • Dystrophin
  • Utrophin
  • Y 26763
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • Animals
  • Benzopyrans (pharmacology)
  • Cell Differentiation (genetics, physiology)
  • Cells, Cultured
  • Disease Models, Animal
  • Dystrophin (deficiency, genetics, metabolism)
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal (metabolism, pathology)
  • Muscular Dystrophy, Animal (genetics, metabolism)
  • Ossification, Heterotopic (genetics, metabolism)
  • Utrophin (deficiency, genetics, metabolism)
  • rho GTP-Binding Proteins (antagonists & inhibitors, metabolism)

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