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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration

¹Department of Movement Sciences, University of Illinois at Chicago, Chicago, Illinois; and ²Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan

Submitted 17 November 2004 ; accepted in final form 11 February 2005

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^–/– mice) or plasminogen demonstrate markedly impaired muscle regeneration after 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 after cardiotoxin injury in wild-type, 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 in wild-type controls. Furthermore, PAI-1^–/– mice demonstrated increased expression of MyoD and developmental myosin after injury as well as accelerated recovery of muscle morphology, protein levels, and muscle force compared with 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 after 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.

muscle injury; muscle repair; urokinase-type plasminogen activator; muscle inflammation; macrophage

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