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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2835-2844
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Plasmin activity is required for myogenesis in vitro and skeletal
muscle regeneration in vivo
Mònica Suelves,
Roser López-Alemany,
Frederic Lluís,
Gloria Aniorte,
Erika Serrano,
Maribel Parra,
Peter Carmeliet, and
Pura Muñoz-Cánoves
From the Centre d'Oncologia Molecular, Institut de
Recerca Oncològica, Barcelona, Spain; and the Center for
Transgene Technology, Flanders Interuniversity, Leuven, Belgium.
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  2-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.
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