Satellite stem cell dysfunction in Duchenne muscular dystrophy

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. We used single cell RNA-sequencing (scRNA-seq) to determine how dystrophin deficiency impacts satellite cell heterogeneity and function. scRNA-seq was performed in satellite cells from mdx and D2-mdx DMD mouse models. DMD satellite cells were disproportionally found within myogenic progenitor clusters and a unique DMD enriched cluster. DMD satellite cells and myogenic progenitors exhibited distinct impairments, including cell death and senescence, respectively. Moreover, dystrophic satellite cells express an impaired myogenic differentiation gene signature and are stalled in their differentiation capacity. We found that inducing autophagy, which is reduced in DMD progenitors, led to enhanced differentiation. Our findings provide molecular evidence of satellite cell dysfunction in DMD and suggest pathways to target and enhance their regenerative capacity.