Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the DMD gene encoding Dystrophin, a critical component of the dystrophin-associated glycoprotein complex that protects the sarcolemma from contraction-induced injury. DMD patients develop progressive degeneration of skeletal and cardiac muscle, leading to severe muscle wasting, loss of ambulation, and ultimately cardiorespiratory failure.
Preclinical animal models have been instrumental in understanding pathogenesis and testing therapies, but the commonly used mdx mouse displays a mild phenotype that does not recapitulate the progressive muscle loss seen in patients. We developed several rat models of DMD, including an exon 52 deletion (Δ52), a duplication of exons 10–17, and a Becker-type Δ45–47 model. DMD rats display progressive muscle loss and weakness, early cardiac dysfunction, and fatal cardiorespiratory failure around 12 months of age. Skeletal muscles exhibit severe fibrosis, adipocyte infiltration, chronic inflammation, fiber atrophy, and fiber type switching, culminating in impaired muscle stem cell function, premature senescence, and regenerative failure.
By analyzing patient samples and rat models, we demonstrated that compromised regenerative capacity in DMD is linked to early stem cell senescence. Notably, extraocular muscles, spared in patients, harbor MuSCs with long-lasting regenerative potential. Single-cell transcriptomics identified Tshr as enriched in extraocular muscles stem cells, with TSHR activity preventing senescence. Pharmacological activation of downstream signaling with Forskolin reduced stem cell senescence, enhanced regenerative potential, promoted myogenesis, and improved muscle function in DMD rats.
Together, these findings highlight novel mechanisms of stem cell senescence in DMD, identify adenylyl cyclase stimulation as a therapeutic avenue, and provide new insights into post-therapy muscle remodeling. We will discuss the implications of these results for the development of effective treatments for DMD and related muscle disorders.