Myofiber-specific inhibition of TGFβ signaling protects skeletal muscle from injury and dystrophic disease in mice

Muscular dystrophy (MD) is a disease characterized by skeletal muscle necrosis and the progressive accumulation of fibrotic tissue. While transforming growth factor (TGF)-beta has emerged as central effector of MD and fibrotic disease, the cell types in diseased muscle that underlie TGFO-dependent pathology have not been segregated. Here, we generated transgenic mice with myofiber-specific inhibition of TGF beta signaling owing to expression of a TGF beta type II receptor dominant-negative (dnTGF beta RII) truncation mutant. Expression of dnTGF beta RII in myofibers mitigated the dystrophic phenotype observed in delta-sarcoglycan-null (Sgcd(-/-)) mice through a mechanism involving reduced myofiber membrane fragility. The dnTGF beta RII transgene also reduced muscle injury and improved muscle regeneration after cardiotoxin injury, as well as increased satellite cell numbers and activity. An unbiased global expression analysis revealed a number of potential mechanisms for dnTGF beta RII-mediated protection, one of which was induction of the antioxidant protein metallothionein (Mt). Indeed, TGF beta directly inhibited Mt gene expression in vitro, the dnTGF beta RII transgene conferred protection against reactive oxygen species accumulation in dystrophic muscle and treatment with Mt mimetics protected skeletal muscle upon injury in vivo and improved the membrane stability of dystrophic myofibers. Hence, our results show that the myofibers are central mediators of the deleterious effects associated with TGF beta signaling in MD.