Muscle and Nerve Injuries
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 is inefficient and is hindered by fibrosis - i.e., scar tissue formation. More importantly, the scar tissue that often 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 overexpression of transforming growth factor ß-1 (TGF-ß1) in various injured tissues is the major cause of fibrosis in animals and humans. Indeed, we have observed that TGF-ßS1 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 decorin can also enhance muscle regeneration makes this molecule more than ideal to improve muscle healing after injury. The overall goal of this research is to investigate the kinetics of TGF-ß1 expression, muscle regeneration, and fibrosis after strain and to delineate the mechanism by which this molecule initiates the fibrosis cascade in skeletal muscle. We are consequently proposing to develop biological approaches based on decorin to efficiently prevent the scarring process by blocking the action of TGF-ß1 and activate muscle regeneration at the adequate time period post-injury. We finally propose to characterize efficient ways to deliver therapeutic and lasting levels of decorin into the injured muscle through the following strategies: (1) direct intramuscular 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.
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