Résumé :
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Communication n° 660 The Plasminogen Activation system (PA system) plays an important role in a wide range of biological processes, especially when extracellular matrix (ECM) degradation and tissue remodeling takes place. Our laboratory has previously shown that several components of the PA system are involved in myogenesis. We have demonstrated the participation of urokinase-type plasminogen activator (uPA), plasminogen (Plg) and alpha-enolase plasminogen receptor (plgR) in in vitro and in vivo models of myogenesis. Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder, consisting in repetitive cycles of muscle degeneration and regeneration and continuous remodeling of the ECM. However, the role of the PA system in DMD has never been investigated. Our aim is to study the potential action of the PA system in the mdx mice, an animal model for the DMD. In this study, we show that uPA and plasmin activity are up-regulated in mdx mice compared to wild type mice, by chromogenic and zymographic assays. Using a specific monoclonal antibody against PlgR, MAb 11G1, raised in our laboratory, we have also found that PlgR expression and activity are elevated in mdx mice, compared to wild type mice. This study constitutes the first indication of PlgR as an important component of skeletal myogenesis, by concentrating and enhancing plasmin generation on the cell surface. Furthermore, we have intercrossed mdx mice with uPA deficient mice. Measuring markers of muscle regeneration in the double mutant mice, we demonstrate that uPA deficiency exacerbates mdx dystrophinopathy. This work represents the first evidence of the role of the PA system in the degenerating muscle of the dystrophic mdx mice. Delineating the mechanisms by which the PA system (uPA, Plg and PlgR) regulate the generation/degeneration process of this dystrophinopathy, will provide useful tools for therapeutic intervention of this disease.
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