Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissu e-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skel etal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-defic ient, and tPA-deficient mice is investigated here. Wild-type and tPA-/- mic e completely repaired experimentally damaged skeletal muscle. In contrast, uPA-/- mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. in addition, uPA-deficient mice accumulated fibrin in the deg enerating muscle fibers; however, the defibrinogenation of uPA-deficient mi ce resulted in a correction of the muscle regeneration defect. A similar se vere regeneration deficit with persistent fibrin deposition was also reprod ucible in plasminogen-deficient mice after injury, suggesting that fibrinol ysis by uPA-mediated plasminogen activation plays a fundamental role in ske letal muscle regeneration. In conclusion, the uPA-plasmin system is identif ied as a critical component of the mammalian skeletal muscle regeneration p rocess, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studi es demonstrate the requirement of an extracellular proteolytic cascade duri ng muscle regeneration in vivo.(Blood. 2001;97:1703-1711) (C) 2001 by The A merican Society of Hematology.