Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even i...

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Autores principales: Mázala, Davi A. G., Hindupur, Ravi, Moon, Young Jae, Shaikh, Fatima, Gamu, Iteoluwakishi H., Alladi, Dhruv, Panci, Georgiana, Weiss-Gayet, Michèle, Chazaud, Bénédicte, Partridge, Terence A., Novak, James S., Jaiswal, Jyoti K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319851/
https://www.ncbi.nlm.nih.gov/pubmed/37402716
http://dx.doi.org/10.1038/s41420-023-01503-0
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author Mázala, Davi A. G.
Hindupur, Ravi
Moon, Young Jae
Shaikh, Fatima
Gamu, Iteoluwakishi H.
Alladi, Dhruv
Panci, Georgiana
Weiss-Gayet, Michèle
Chazaud, Bénédicte
Partridge, Terence A.
Novak, James S.
Jaiswal, Jyoti K.
author_facet Mázala, Davi A. G.
Hindupur, Ravi
Moon, Young Jae
Shaikh, Fatima
Gamu, Iteoluwakishi H.
Alladi, Dhruv
Panci, Georgiana
Weiss-Gayet, Michèle
Chazaud, Bénédicte
Partridge, Terence A.
Novak, James S.
Jaiswal, Jyoti K.
author_sort Mázala, Davi A. G.
collection PubMed
description Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.
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spelling pubmed-103198512023-07-06 Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD Mázala, Davi A. G. Hindupur, Ravi Moon, Young Jae Shaikh, Fatima Gamu, Iteoluwakishi H. Alladi, Dhruv Panci, Georgiana Weiss-Gayet, Michèle Chazaud, Bénédicte Partridge, Terence A. Novak, James S. Jaiswal, Jyoti K. Cell Death Discov Article Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD. Nature Publishing Group UK 2023-07-04 /pmc/articles/PMC10319851/ /pubmed/37402716 http://dx.doi.org/10.1038/s41420-023-01503-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mázala, Davi A. G.
Hindupur, Ravi
Moon, Young Jae
Shaikh, Fatima
Gamu, Iteoluwakishi H.
Alladi, Dhruv
Panci, Georgiana
Weiss-Gayet, Michèle
Chazaud, Bénédicte
Partridge, Terence A.
Novak, James S.
Jaiswal, Jyoti K.
Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title_full Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title_fullStr Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title_full_unstemmed Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title_short Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
title_sort altered muscle niche contributes to myogenic deficit in the d2-mdx model of severe dmd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319851/
https://www.ncbi.nlm.nih.gov/pubmed/37402716
http://dx.doi.org/10.1038/s41420-023-01503-0
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