Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis

Skeletal muscle fibrosis is strongly associated with the differentiation of its resident multipotent fibro/adipogenic progenitors (FAPs) toward the myofibroblast phenotype. Although transforming growth factor type β (TGF-β) signaling is well-known for driving FAPs differentiation and fibrosis, due to its pleiotropic functions its complete inhibition is not suitable for treating fibrotic disorders such as muscular dystrophies. Here, we describe that TGF-β operates through the mechanosensitive transcriptional regulators Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) to determine the myofibroblast fate of FAPs and skeletal muscle fibrosis. Spatial transcriptomics analyses of dystrophic and acute injured muscles showed that areas with active fibrosis and TGF-β signaling displayed high YAP/TAZ activity. Using a TGF-β-driven fibrotic mouse model, we found that activation of YAP/TAZ in activated FAPs is associated with the fibrotic process. Mechanistically, primary culture of FAPs reveals the remarkable ability of TGF-β1 to activate YAP/TAZ through its canonical SMAD3 pathway. Moreover, inhibition of YAP/TAZ, either by disrupting its activity (with Verteporfin) or cellular mechanotransduction (with the Rho inhibitor C3 or soft matrices), decreased TGF-β1-dependent FAPs differentiation into myofibroblasts. In vivo, administration of Verteporfin in mice limits the deposition of collagen and fibronectin, and the activation of FAPs during the development of fibrosis. Overall, our work provides robust evidence for considering YAP/TAZ as a potential target in muscular fibroproliferative disorders.NEW & NOTEWORTHY The understanding of the nuclear factors governing the differentiation of muscular fibro/adipogenic progenitors (FAPs) into myofibroblasts is in its infancy. Here, we comprehensively elucidate the status, regulation, and role of the mechanotransducers Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in the muscular fibrotic process. Our findings reveal that inhibiting cellular mechanotransduction limits FAP differentiation and the extent of muscular fibrosis exerted by transforming growth factor type β (TGF-β). This research shed new lights on the molecular mechanisms dictating the cell fate of FAPs and the muscular fibrosis.