Plasmin activity is required for myogenesis in vitro and skeletal muscle regeneration in vivo.
Plasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum and is implicated in biologic processes dependent upon proteolytic activity, such as tissue remodeling and cell migration. Active plasmin is generated from proteolytic cleavage of the zymogen plasminogen (Plg) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Here, we have investigated the role of plasmin in C2C12 myoblast fusion and differentiation in vitro, as well as in skeletal muscle regeneration in vivo, in wild-type and Plg-deficient mice. Wild-type mice completely repaired experimentally damaged skeletal muscle. In contrast, Plg(-/-) mice presented a severe regeneration defect with decreased recruitment of blood-derived monocytes and lymphocytes to the site of injury and persistent myotube degeneration. In addition, Plg-deficient mice accumulated fibrin in the degenerating muscle fibers; however, fibrinogen depletion of Plg-deficient mice resulted in a correction of the muscular regeneration defect. Because we found that uPA, but not tPA, was induced in skeletal muscle regeneration, and persistent fibrin deposition was also reproducible in uPA-deficient mice following injury, we propose that fibrinolysis by uPA-dependent plasmin activity plays a fundamental role in skeletal muscle regeneration. In summary, we identify plasmin as a critical component of the mammalian skeletal muscle regeneration process, possibly by preventing intramuscular fibrin accumulation and by contributing to the adequate inflammatory response after injury. Finally, we found that inhibition of plasmin activity with alpha2-antiplasmin resulted in decreased myoblast fusion and differentiation in vitro. Altogether, these studies demonstrate the requirement of plasmin during myogenesis in vitro and muscle regeneration in vivo.
Suelves
Mònica
M
Centre d'Oncologia Molecular, Institut de Recerca Oncològica, Barcelona, Spain.
López-Alemany
Roser
R
Lluís
Frederic
F
Aniorte
Gloria
G
Serrano
Erika
E
Parra
Maribel
M
Carmeliet
Peter
P
Muñoz-Cánoves
Pura
P
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005340:Fibrinogen / Q000494:pharmacology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D005342:Fibrinolysis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018008:Myogenin / Q000187:drug effects / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
C503801:Myog protein, mouse; D018008:Myogenin; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator