Single nuclei transcriptomics of muscle reveals intra-muscular cell dynamics linked to dystrophin loss and rescue

• DOI: 10.1038/s42003-022-03938-0
• Publication Date: 2022-09-19T18:08:37Z
• Authors: Deirdre D. Script...; Kevin N. Chesmore; Florian Barthélémy; Richard T. Wang; Shirley Nieves-Ro...; Derek W. Wang; Ekaterina I. Mokh...; Emilie D. Douine; Jijun Wan; Isaiah Little; Laura N. Rabichow; Stanley F. Nelson; M. Carrie Miceli
• Keywords: Exon skipping; mdx mouse; Utrophin

Abstract In Duchenne muscular dystrophy, dystrophin loss leads to chronic muscle damage, dysregulation of repair, fibro-fatty replacement, and weakness. We develop methodology efficiently isolate individual nuclei from minute quantities frozen skeletal muscle, allowing single sequencing irreplaceable archival samples very small samples. apply this method identify cell gene expression dynamics within human DMD mdx mouse characterizing effects rescue by exon skipping therapy at resolution. 23 events are directly observed increased in myonuclei treated mice. describe partial type IIa IIx myofibers, expansion an MDSC-like myeloid population, recovery repair/remodeling M2-macrophage, repression inflammatory POSTN1 + fibroblasts response restoration. Use enables exploration cellular transcriptomic mechanisms repair intact environment. Our initial findings will scaffold our future work more examine dystrophies putative pathways.