Matrix Nonlinear Viscoelasticity Regulates Skeletal Myogenesis through MRTF Nuclear Localization and Nuclear Mechanotransduction

Mechanically sensitive tissues (e.g., skeletal muscles) greatly need mechanical stimuli during the development and maturation. The extracellular matrix (ECM) mediates these signals through nonlinear viscoelasticity of collagen networks that are predominant components of the ECM. However, the interactions between cells and ECM form a feedback loop, and it has not yet been possible to determine the degree to which, if any, of the features of matrix nonlinear viscoelasticity affect skeletal muscle development and regeneration. In this study, a nonlinear viscoelastic feature (i.e., strain-enhanced stress relaxation (SESR)) in normal skeletal muscles is observed, which however is almost absent in diseased muscles from Duchenne muscular dystrophy mice. It is recapitulated such SESR feature in vitro and separated the effects of mechanical strain and ECM viscoelasticity on myoblast response by developing a collagen-based hydrogel platform. Both strain and stress relaxation induce myogenic differentiation and myotube formation by C2C12 myoblasts, and myogenesis is more promoted by applying SESR. This promotion can be explained by the effects of SESR on actin polymerization-mediated myocardin related transcription factor (MRTF) nuclear localization and nuclear mechanotransduction. This study represents the first attempt to investigate the SESR phenomenon in skeletal muscles and reveal underlying mechanobiology, which will provide new opportunities for the tissue injury treatments.