Profound cellular defects attribute to muscular pathogenesis in the rhesus monkey model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by mutations in the DMD gene. Muscle fibers rely on the coordination of multiple cell types for repair and regenerative capacity. To elucidate the cellular and molecular changes in these cell types under pathologic conditions, we generated a rhesus monkey model for DMD that displays progressive muscle deterioration and impaired motor function, mirroring human conditions. By leveraging these DMD monkeys, we analyzed freshly isolated muscle tissues using single-cell RNA sequencing (scRNA-seq). Our analysis revealed changes in immune cell landscape, a reversion of lineage progressing directions in fibrotic fibro-adipogenic progenitors (FAPs), and TGF-β resistance in FAPs and muscle stem cells (MuSCs). Furthermore, MuSCs displayed cell-intrinsic defects, leading to differentiation deficiencies. Our study provides important insights into the pathogenesis of DMD, offering a valuable model and dataset for further exploration of the underlying mechanisms, and serves as a suitable platform for developing and evaluating therapeutic interventions. [Display omitted] • Generation of DMD monkey model recapitulating the pathogenesis of human patients • The immune cell landscape undergoes highly dynamic changes in DMD monkeys • Abnormal differentiation of FAPs causes TGF-β-independent fibrosis • Profound muscle stem cell defects contribute to the muscle dysfunction of DMD A DMD rhesus monkey model exhibits profound changes in immune cells, fibro-adipogenic progenitors (FAPs), and muscle stem cells at the early stage of the disease, constituting a suitable model for investigating disease mechanisms. [ABSTRACT FROM AUTHOR]