Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration.
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.
Koh
Timothy J
TJ
Department of Movement Sciences (M/C 194), University of Illinois at Chicago, 901 W. Roosevelt Rd., Chicago, Illinois 60608, USA. tjkoh@uic.edu
Bryer
Scott C
SC
Pucci
Augustina M
AM
Sisson
Thomas H
TH
D000818:Animals; D004179:Cobra Cardiotoxin Proteins / Q000494:pharmacology; D006614:Hindlimb; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency*; D010960:Plasminogen Activators / Q000378:metabolism; D012038:Regeneration; D014034:Toes; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D004179:Cobra Cardiotoxin Proteins; D009124:Muscle Proteins; D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator