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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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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. |
format | Online Article Text |
id | pubmed-10319851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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