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

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-/-...

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Autores principales: Mu, Xiaodong, Lin, Chi-Yi, Hambright, William S., Tang, Ying, Ravuri, Sudheer, Lu, Aiping, Matre, Polina, Chen, Wanqun, Gao, Xueqin, Cui, Yan, Zhong, Ling, Wang, Bing, Huard, Johnny
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803538/
https://www.ncbi.nlm.nih.gov/pubmed/33361519
http://dx.doi.org/10.18632/aging.202413
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author Mu, Xiaodong
Lin, Chi-Yi
Hambright, William S.
Tang, Ying
Ravuri, Sudheer
Lu, Aiping
Matre, Polina
Chen, Wanqun
Gao, Xueqin
Cui, Yan
Zhong, Ling
Wang, Bing
Huard, Johnny
author_facet Mu, Xiaodong
Lin, Chi-Yi
Hambright, William S.
Tang, Ying
Ravuri, Sudheer
Lu, Aiping
Matre, Polina
Chen, Wanqun
Gao, Xueqin
Cui, Yan
Zhong, Ling
Wang, Bing
Huard, Johnny
author_sort Mu, Xiaodong
collection PubMed
description 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. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies.
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spelling pubmed-78035382021-01-15 Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice Mu, Xiaodong Lin, Chi-Yi Hambright, William S. Tang, Ying Ravuri, Sudheer Lu, Aiping Matre, Polina Chen, Wanqun Gao, Xueqin Cui, Yan Zhong, Ling Wang, Bing Huard, Johnny Aging (Albany NY) Research Paper 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. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies. Impact Journals 2020-12-23 /pmc/articles/PMC7803538/ /pubmed/33361519 http://dx.doi.org/10.18632/aging.202413 Text en Copyright: © 2020 Mu et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Mu, Xiaodong
Lin, Chi-Yi
Hambright, William S.
Tang, Ying
Ravuri, Sudheer
Lu, Aiping
Matre, Polina
Chen, Wanqun
Gao, Xueqin
Cui, Yan
Zhong, Ling
Wang, Bing
Huard, Johnny
Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title_full Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title_fullStr Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title_full_unstemmed Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title_short Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
title_sort aberrant rhoa activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803538/
https://www.ncbi.nlm.nih.gov/pubmed/33361519
http://dx.doi.org/10.18632/aging.202413
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