Year: 2023
Type: article
Abstract: 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.
Source: Cell Death Discovery
Institutions: Children's National, Towson University, Jeonbuk National University Hospital, Jeonbuk National University, Lyon 1 Université, Centre National de la Recherche Scientifique, Inserm, Institut NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, George Washington University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,390
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Foundation to Eradicate Duchenne, Muscular Dystrophy Association, Towson University, Children's National Hospital, Agence Nationale de la Recherche, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Congressionally Directed Medical Research Programs
Awards: USE OF MACROPHAGES FOR TARGETED DUAL ANTISENSE DELIVERY TO TREAT DMD, G1313942571, G2334543714, Integration of signaling pathways controlling muscle fibrosis, District of Columbia Intellectual and Developmental Disabilities Research Center, Understanding the mechanism and role of cell membrane repair in Miyoshi Myopathy, G4658953696, G5590494402, Use of Macrophages for Targeted Dual Antisense Delivery to Treat DMD, TARGETED CELL-BASED GENE THERAPIES FOR PERSISTENT EXON SKIPPING AND DYSTROPHIN RESTORATION IN DMD, Genetics and Genomics of Muscle Postdoctoral Training Program, Targeted Cell-Based Gene Therapies for Persistent Exon Skipping and Dystrophin Restoration in DMD, District of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC)
OpenAlex ID: W4383069975