Résumé :
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Communication n° 206 Muscle fibers attach to laminin in the basal lamina using two mechanisms that have been studied in this work. The first one involves dystrophin-associated protein complex (DAPC) and the second one implies muscle-specific alpha7beta1 integrin. The DAPC and the alpha7beta1 integrin both participate in the molecular continuity between the extracellular matrix and myofibers, which is essential for muscle membrane structural and functional integrity. In humans, defects in the dystrophin gene result in a lack of dystrophin, which weakens muscle fiber association with the surrounding basal lamina and underlies Duchenne and Becker muscular dystrophies. The absence of dystrophin is followed by persistence of a homologous protein called utrophin and by partially disruption of membrane-bound nNOS. The NO precursor is provided by L-arginine (L-Arg), which is the nNOS substrate. If muscle fibers produce sufficient level of nNOS, elevated L-Arg concentrations could influence NO synthesis and perhaps improve muscle membrane integrity. To investigate this point, treatment of a murine model of dystrophin deficiency, i.e. mdx mouse, with L-Arg has been underway. Utrophin, different members of the DAPC and alpha7B integrin were analysed in 5- and 13-week-old cardiac muscle and diaphragm by Western blot and immunofluorescent detection. Here, we describe specific protein changes and potential associated improvements in muscle morphology induced by L-Arg treatment in dystrophin-deficient muscles. In the two studied muscles, the alpha7B integrin subunit was increased in 5-week-old treated mice. Interestingly, the diaphragm histopathological appearance was significantly improved by L-arginine administration with more uniform fiber diameters, reduced number of central nuclei and low signs of lymphocytic invasion. These results highlight a possible way to compensate for dystrophin deficiency via alpha7beta1 integrin and suggest that only within the short period at around 5-week-old when a large number of muscle fibers undergoes degeneration, drug candidates like L-Arg may have a therapeutic effect on dystrophic process.
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