Muscle stem cells in Duchenne muscular dystrophy exhibit molecular impairments and altered cell fate trajectories impacting regenerative capacity

作者：Jules A Granet, Rebecca Robertson, Alessio A Cusmano, Romina L. Filippelli, Tim O Lorenz, Shulei Li, Moein Yaqubi, Jo Anne Stratton, Natasha C. Chang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07755-1 · 被引用次数：19 · 研究领域：Muscle Physiology and Disorders、Telomeres, Telomerase, and Senescence、Tissue Engineering and Regenerative Medicine

Satellite cells are muscle-resident stem cells that maintain and repair muscle. Increasing evidence supports the contributing role of satellite cells in Duchenne muscular dystrophy (DMD), a lethal degenerative muscle disease caused by loss of dystrophin. However, whether or not satellite cells exhibit dysfunction due to loss of dystrophin remains unresolved. Here, we used single-cell RNA-sequencing (scRNA-seq) to determine how dystrophin deficiency impacts the satellite cell transcriptome and cellular composition by comparing satellite cells from mdx and the more severe D2-mdx DMD mouse models. DMD satellite cells were disproportionally found within myogenic progenitor clusters and a previously uncharacterized DMD-enriched cluster. Despite exposure to different dystrophic environments, mdx and D2-mdx satellite cells exhibited overlapping dysregulation in gene expression and associated biological pathways. When comparing satellite stem cell versus myogenic progenitor populations, we identified unique dysfunctions between DMD and healthy satellite cells, including apoptotic cell death and senescence, respectively. Pseudotime analyses revealed differences in cell fate trajectories, indicating that DMD satellite cells are stalled in their differentiation capacity. In vivo regeneration assays confirmed that DMD satellite cells exhibit impaired myogenic gene expression and cell fate dynamics during regenerative myogenesis. These defects in differentiation capacity are accompanied b...