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1 Department of Movement Sciences, University of Illinois at Chicago, Chicago, IL, USA
2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: tjkoh{at}uic.edu.
Skeletal muscle possesses a remarkable capacity for regeneration. Although the regulation of this process at the molecular level remains largely undefined, the plasminogen system appears to play a critical role. Specifically, mice deficient in either urokinase-type plasminogen activator (uPA) or plasminogen demonstrate markedly impaired muscle regeneration following injury. In the present study, we tested the hypothesis that loss of the primary inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), would improve muscle regeneration. Repair of the extensor digitorum longus muscle was assessed following cardiotoxin injury in wild-type, uPA deficient (uPA-/-) and PAI-1 deficient (PAI-1-/-) mice. As expected, there was no uPA activity in the injured muscles of uPA-/- mice, and muscles from these transgenic animals demonstrated impaired regeneration. On the other hand, uPA activity was increased in injured muscle from PAI-1-/- mice to a greater extent than wild-type controls. Furthermore, PAI-1-/- mice demonstrated increased expression of MyoD and developmental myosin following injury as well as accelerated recovery of muscle morphology, protein levels and muscle force compared to wild-type animals. The injured muscles of PAI-1 null mice also demonstrated increased macrophage accumulation, contrasting with impaired macrophage accumulation in uPA deficient mice. The extent of macrophage accumulation correlated with both the clearance of protein following injury and the efficiency of regeneration. Taken together, these results indicate that PAI-1 deficiency promotes muscle regeneration, and this protease inhibitor represents a therapeutic target for enhancing muscle regeneration.
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