BLOCKING MYOSTATIN SIGNALLING PATHWAY WITH MYOSTATIN PROPEPTIDE AND FOLLISTATIN: NOVEL APPROACHES TO IMPROVE SKLETAL MUSCLE HEALING

The complete recovery of injured skeletal muscle has posed a constant challenge for orthopaedic physician. Once injured, skeletal muscle is able to undergo regeneration from satellite cells; nevertheless, in the serious injured muscle, the formation of fibrosis often impedes effective muscle regeneration and resulted in an incomplete muscle healing. Therefore, to develop biological approaches to improve muscle healing, it is crucial to better understand the mechanisms of the skeletal muscle fibrosis. In the current studies, we found that myostatin (MSTN), a member of TGF-â family, plays a role in the formation of skeletal muscle fibrosis, besides the other putative fibrosis stimulator, TGF-â1. In vitro, MSTN directly stimulated the proliferation of fibroblasts and their productions of fibrotic proteins. In vivo, after laceration injury, gastronemius muscles of MSTN-/- mice showed less fibrosis and better muscle regeneration than wide-type (WT) counterparts. Considering MSTN as a therapeutic target of skeletal muscle healing, we found that inhibitors of MSTN, MSTN propeptide (MPRO) and follistatin, effectively blocked MSTN signaling and improved skeletal muscle healing after injured. We used adeno-associated virus (AAV)-mediated MPRO cDNA to successfully deliver MPRO in vivo and improve skeletal muscle healing of normal mice after laceration, and ameliorate dystrophic pathology of mdx/SCID mice. Furthermore, our results demonstrated FLST overexpression (FLST/OE) mice exhibited decreased fibrosis and increased muscle regeneration in injured skeletal muscle as compared to wild-type (WT) mice. Moreover, muscle progenitor cells (MPCs) isolated from MSTN-/- and FLST/OE mice significantly regenerated more myofibers than MPCs obtained from WT mice, when transplanted into dystrophic muscles. Collectively, our results suggested that MSTN directly stimulated fibrosis in the injured skeletal muscle; blocking MSTN signaling with MPRO or FLST improved skeletal muscle healing after laceration injury; blocking MSTN signaling in donor MPCs significantly enhanced the success of cell transplantation into dystrophic muscles. Our studies not only uncovered some of the mechanisms implicated in skeletal muscle fibrosis and regeneration, and help the development of new therapeutic approach for promoting the healing of injured or diseased skeletal muscle, but also render a new sight of how to obtain robust genetically modified cell populations for cell therapy.