Transforming Growth Factor-β Signalling in the Regulation of Skeletal Muscle Regeneration, Fibrosis and Function

Muscle wasting diseases are characterized by the loss of muscle mass, function and regenerative capacity, which negatively affects the quality of life. Transforming growth factor-beta (TGF-β) superfamily members, such as TGF-β, myostatin and activin A, play an important role in reducing muscle mass (atrophy), force and regenerative capacity. Targeting TGF-β signalling is a potential approach to treat muscle wasting. In vivo studies of this thesis show that simultaneous knockout of TGF-β type I receptors Acvr1b and Tgfbr1 in a skeletal muscle-specific manner induced muscle hypertrophy, improved muscle regeneration upon acute injury and increased muscle contractile force. Knockout of both receptors in mice induced more differentially expressed genes in fast-type muscle than slow-type muscle, which were related to muscle growth, contraction, cytoskeleton and metabolism. However, myofibre size increment was not proportional to the increase in contractile force in gastrocnemius. Strikingly, the increase in myofibre size was accompanied by an increase in oxidative metabolism in muscles lacking both type I receptors. In vitro studies show that myotubes produced more collagen I protein than myoblasts. Both TGF-β1 and 3 stimulated collagen production in muscle cells. Noteworthy, siRNA-mediated knockdown of both type I receptors in myotubes reduced their diameter and protein synthesis process, which was associated with the increased expression level of Sntb1 which encodes a unit of dystrophin-glycoprotein complex. Taken together, we identified the regulatory role of TGF-β signalling with respect to muscle adaptation which contributes to the development of treatments for muscle wasting.