Résumé :
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Urocortins are structurally related peptides of the corticotrophin-releasing factor (CRF), which has been widely implicated in responses to physical, emotional and environmental stress. Recently, it has been reported that a CRF-receptor-2 (CRFR2) agonist increased muscle mass and slowed disease progression in the mdx mouse model. Here, we report on our investigations on urocortins in protecting mdx muscle from necrosis and on the mechanism involved. Three week-old mdx5Cv mice were treated daily by sub-cutaneous injection for 2 weeks with either urocortin 1 at 300 ?g/kg, urocortin 2 (30, 100 or 300 ?g/kg), or vehicle. Isometric force recordings of the triceps surae (comprising soleus, plantaris and gastrocnemius muscles) showed that contraction and relaxation kinetics were shorter than in untreated mice. Moreover, the force-frequency curve was shifted to the right, suggesting a change in the calcium homeostasis or in the distribution of fibres toward a faster phenotype. Interestingly, hindlimb muscles from mice receiving urocortins displayed a higher resistance to mechanical stress and muscle mass was significantly increased. Histology demonstrated that urocortins remarkably protected diaphragm, EDL and soleus muscles from necrosis. Finally, urocortins administration lowered plasma creatine kinase levels up to 49% compared with vehicle. In addition, basal calcium influx was measured in whole dystrophic muscle (EDL and soleus) and in diaphragm strips. Urocortin 2 concentration-dependently decreased the permeability of the dystrophic muscle to calcium by 20-40%. This effect was completely abolished by the selective CRFR2 antagonist astressin2-B or an inhibitor of protein kinase A (PKA) while addition of forskolin, an activator of adenylate cyclase, mimicked the effect of urocortin 2. We conclude that urocortins improve both the structure and the function of dystrophic skeletal muscle via the stimulation of a cAMP/PKA-dependent signal transduction pathway. Thus, urocortins should be considered as potential candidates to counteract the impairment of calcium homeostasis observed in Duchenne Muscular Dystrophy.
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