TY - JOUR
T1 - Aberrant RhoA activation in macrophages increases senescence- associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
AU - Mu, Xiaodong
AU - Lin, Chi Yi
AU - Hambright, William S.
AU - Tang, Ying
AU - Ravuri, Sudheer
AU - Lu, Aiping
AU - Matre, Polina
AU - Chen, Wanqun
AU - Gao, Xueqin
AU - Cui, Yan
AU - Zhong, Ling
AU - Wang, Bing
AU - Huard, Johnny
N1 - Publisher Copyright:
© 2020 Mu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/12/31
Y1 - 2020/12/31
N2 - 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.
AB - 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.
KW - cellular senescence
KW - chronic inflammation
KW - heterotopic ossification
KW - muscle dystrophy
KW - muscle stem cell
UR - http://www.scopus.com/inward/record.url?scp=85098872766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098872766&partnerID=8YFLogxK
U2 - 10.18632/aging.202413
DO - 10.18632/aging.202413
M3 - Article
C2 - 33361519
AN - SCOPUS:85098872766
SN - 1945-4589
VL - 12
SP - 24853
EP - 24871
JO - Aging
JF - Aging
IS - 24
ER -