Enhancement of Skeletal Muscle Repair by the Urokinase Type Plasminogen Activator System

Skeletal muscle injuries, caused by intense exercise or trauma, are among the most common injuries in military personnel. Enhancement of muscle repair following injury would minimize time lost and maximize performance during training and combat. We and others have published data demonstrating that the extracellular protease urokinase-type plasminogen activator uPA is required for efficient muscle repair, although the underlying mechanisms remain to be elucidated. In this progress report, we present data indicating that satellite cell fusion during muscle regeneration is impaired in uPA null mice, and accelerated in mice deficient in the inhibitor of uPA, PAI-1, compared to wild-type mice. In vitro experiments have demonstrated that uPA causes a dose-dependent increase in the proliferation and migration of wild-type satellite cells. Western blot analysis indicated that phosphorylation of the receptor of HGF, c-met, is impaired in injured muscle of uPA null mice and increased in muscle of PAI-1 null mice. Finally, administration of exogenous uPA has been shown to rescue muscle regeneration in uPA null mice. Taken together, these data support the hypothesis that satellite cell activity is regulated by the balance of uPA and PAI-1, through activation of HGF. Findings from continued work on this project will provide insight into potential manipulation of components of the plasminogen system as a way to enhance muscle repair. Enhancing muscle repair following injury would minimize time lost due to muscle injury both during training and combat, and maximize performance following return from injury.