Rat Duchenne muscular dystrophy models for preclinical studies and deciphering tissue repair mechanisms

Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by mutations in the Dmd gene, resulting in the absence of Dystrophin, a key protein protecting muscle cells. DMD leads to progressive skeletal and cardiac muscle degeneration, culminating in cardiac and respiratory failure. Traditional animal models, like mdx mice, exhibit a mild phenotype unlike the severe muscle loss seen in DMD patients. A newly developed rat model with a deletion in exon 52 shows progressive muscle tissue loss, cardiac dysfunction, and death by 12 months. These rats exhibit severe muscle fibrosis, inflammation, and stem cell dysfunction. Analysis of patient samples and the rat model revealed early muscle stem cell senescence. Notably, extraocular muscles (EOMs) in patients, which are spared by DMD, have stem cells with strong regenerative potential. Single-cell transcriptomics identified high expression of the TSH receptor (Tshr) in EOM stem cells, with TSHR activity preventing senescence. Forskolin, which activates TSHR signaling, improved muscle function in DMD rats by reducing stem cell senescence and enhancing regeneration, suggesting a new therapeutic approach.