Dmd clinical therapies i

Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disease that causes premature death and for which no cure exists. We have shown previously that in vitro treatment of dystrophic myotubes and excised muscles with diapocynin, a dimer of the classically used NADPH oxidase (NOX) inhibitor apocynin, ameliorated several molecular events involved in DMD pathogenesis, of which ROS production, phospholipase A2 activity, Ca2+ influx and sarcolemmal integrity. Here, we report on the in vivo effects of diapocynin and apocynin in mdx5Cv dystrophic mice, a model of DMD. Diapocynin but not apocynin enhanced spontaneous locomotor activity, rescued voluntary wheel running capabilities, and ameliorated diaphragm structure of dystrophic mice. Diapocynin and apocynin were equally potent at increasing the resistance to fatigue of triceps surae muscles exposed to repeated isometric contractions in situ and at preserving sarcolemmal integrity as evidenced by Evans blue dye uptake. Furthermore, microarray analyses showed a tendency of the treatments to correct gene expression in dystrophic mice. To further validate NOXes as novel therapeutic target in DMD, novel tools for monitoring NOX activity in muscle fibres have been evaluated and new NOX2 and NOX4 inhibitors have been tested in dystrophic cultures and isolated muscles. The results of this study show the potential of targeting NOXes in DMD animal models.