IMPROVING MUSCLE HEALING THROUGH PREVENTION OF FIBROSIS

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Muscle injuries, especially pulls and strains, present a challenging problem in traumatology and are among the most common and most often disabling injuries in athletes. The injured muscles are capable of healing, although very slowly and often with incomplete functional recovery. The injured muscle can promptly initiate regeneration for the healing process, but that process in inefficient and is hindered by fibrosis ie, scar tissue formation. More importantly, the scar tissue that replaces the damaged myofibers is a potential contributing factor in the tendency of strains to recur. We have identified various growth factors capable of enhancing myoblast proliferation and differentiation, and their delivery within injured muscle improves muscle regeneration, but the development of fibrosis still limits recovery. On the other hand, it has been reported that the over expression of transforming growth factor (TGF-) in various injured tissues is the major cause of fibrosis in animals and humans. Indeed, we have observed that TGF- plays a central role in skeletal muscle fibrosis and, more importantly, that the use of antifibrosis agents, such as decorin, that inactivate the effect of this molecule can reduce muscle fibrosis and consequently improve muscle healing to a near complete recovery after injuries. Our recent observation that decor in can also enhance muscle regeneration makes this molecule more than ideal to improve muscle healing after injury. We therefore propose to investigate the kinetics of TGF- expression, muscle regeneration, and fibrosis after strain and to delineate the mechanism by which this molecule initiates the fibrosis cascade in skeletal muscle. We will consequently develop biological approaches based on decor in to efficiently prevent the scarring process by blocking the action of TGF- and activate muscle regeneration at the adequate time period post-injury. We finally propose to characterize efficient way to deliver therapeutic and lasting levels of decor in into the injured muscle through the following strategies: (1) direct intramuscularly injection of the recombinant proteins and (2) in vivo gene delivery by gene vectors. These studies should further our understanding of the muscle healing process, expedite the methodology to promote efficient muscle healing, and contribute to the development of innovative therapies for other muscle diseases, such as dystrophies.