Aberrant RhoA activation in macrophages increases senescence- associated secretory phenotypes and ectopic calcification in muscular dystrophic mice

Xiaodong Mu, Chi Yi Lin, William S. Hambright, Ying Tang, Sudheer Ravuri, Aiping Lu, Polina Matre, Wanqun Chen, Xueqin Gao, Yan Cui, Ling Zhong, Bing Wang, Johnny Huard

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (dKO, dystrophin-/-; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in dKO mice. However, the cellular identity of these RhoA+ cells, and the role that RhoA plays in the chronic inflammation-associated pathologies has not been elucidated. Here, we report that CD68+ macrophages are highly prevalent at the sites of ectopic calcification of dKO mice, and that these macrophages highly express RhoA. Macrophages from dKO mice feature a shift towards a more pro- inflammatory M1 polarization and an increased expression of various senescence-associated secretory phenotype (SASP) factors that was reduced with the RhoA/ROCK inhibitor Y-27632. Further, systemic inhibition of RhoA activity in dKO mice led to reduced number of RhoA+/CD68+ cells, as well as a reduction in fibrosis and ectopic calcification.

Original languageEnglish (US)
Pages (from-to)24853-24871
Number of pages19
JournalAging
Volume12
Issue number24
DOIs
StatePublished - Dec 31 2020

Keywords

  • cellular senescence
  • chronic inflammation
  • heterotopic ossification
  • muscle dystrophy
  • muscle stem cell

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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