Résumé :
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L-Arginine was proposed as a potential pharmacological tool in Duchenne muscular dystrophy (DMD), a progressive-muscle wasting disease due to mutations in the dystrophin gene. Despite the beneficial effect on L-arginine on muscle weakness and force, mechanisms by each this molecule acts on muscle remain poorly investigated. Here, we showed that L-Arginine administration to 5 week-old mdx mice improves Ca2+-sparks’s properties with a significant increase in spark amplitude, a shorter rise-time and increase spatial spread. In the other hand we demonstrate that L-arginine treatment decreases inflammatory secreted cytokine IL-1?, IL-6 and TNF-? targeted to dystrophic muscle fibres. This leads to decrease level and activity of NF-kB and its targeted proteins such as the muscle specific metalloproteinases MMP-2 and MMP-9. The ?-dystroglycan (a key transmembrane glycoprotein of the dystrophin glycoprotein complex) which anchors utrophin to sarcolemma is a target protein of the MMP-2 and MMP-9 in mdx muscle. Increase activiy of MMPs promotes an abnormal cleavage of the ?-dystroglycan into a ~30 kDa form. Acting on NF-kB/MMPs cascade L-arginine promotes a better membrane stability of ?-dystroglycan/utrophin couple and re-localizes nNOS in subsarcolemmal compartment of the dystrophic fibres which could explain the beneficial effect on resistance to contraction-induced mechanical stress observed in treated muscle. In conclusion our study points on the involved signaling cascades targeted by L-arginine in dystrophin-deficient muscle and strengthens the use of L-arginine as a potential pharmacological tool in Duchenne muscular dystrophies and also enlarges its use in other muscle-inflammation mediated myopathies.
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