Enhanced signs of oxidative stress and ROS are present in mdx mouse muscle before the onset of pathology signs (27).

The high ROS production might be related to inflammatory cell infiltrations, to an inability of dystrophic muscle to properly respond to oxidative injury, or to mitochondrial sufferance. However, recent evidences suggest that a cytoskeleton-dependent stretchactivation of NADPH oxidase (NOX-2) accounts Inhibitors,research,lifescience,medical for an unbalanced production of the highly reactive superoxide anion (O2 -) specie and oxidative stress (X-ROS) in dystrophic muscle and heart (28). According to this view, we have described that O2 – production is higher in exercised versus non-exercised mdx muscles (29). Interestingly, a chronic and early treatment of exercised mdx mice with enalapril, a drug blunting angiotensin-II production by inhibiting angiotensin-converting enzyme (ACE), leads to a dose-dependent reduction of O2 – in muscles, along with a reduction of activated Inhibitors,research,lifescience,medical NF-kB (30). Angiotensin-II is the main endogenous regulator of NOX-2, supporting the interest of this latter Inhibitors,research,lifescience,medical as specific target. Interestingly, Angiotensin-II is also involved in fibrotic process in skeletal muscle and heart (see dedicated paragraph), and ACE-inhibitors and antagonists of the AT1 receptors, such as losartan, are already used in DMD patients to control cardiomyopathy (2, 31, 32). The early anti-oxidant effect of

enalapril may help the design of proper anti-oxidant strategies, as most of the approaches used had limited translational

impact for the wide and aspecific action of the scavenger used or the limited knowledge about the ROS targets in the dystrophic muscles. In this sense, important findings have been obtained in mdx mouse phenotype Inhibitors,research,lifescience,medical with N-acetyl-cysteine (NAC), a well known anti-oxidant Inhibitors,research,lifescience,medical compound. NAC has been described to protect dystrophic myofibers against eccentric muscle damage and to contrast abnormal calcium influx, then linking oxidative stress to key pathological features (33). A more recent study showed the direct ability of NAC to contrast the enhanced thiol R406 oxidation in mdx muscles Adenylyl cyclase providing additional evidences about ROS targets and their impact in signalling in skeletal muscle (34). NAC is a rather inexpensive and safe drug that may deserve a more detailed clinical study in DMD patients. Other antioxidants such as idebenone, acts as Coenzyme Q, and has been mainly tested for its effects at heart level (35), while green tea extracts ([-]-epigallocatechin gallate) are subject of an intense research by Ruegg’s group and other laboratories. Early addition of green tea extracts to diet significantly reduced muscle damage in the EDL muscle of 4 week old mice and improved muscle function in 8 week old mice after 5 weeks of treatment; a synergic effect with low-intensity exercise has also been described (36-38).