The primary genetic defect of DMD is dystrophin gene mutation. Dystrophin is a sub-sarcolemmal structural protein essential for Fuziline muscle cell membrane integrity and signal transduction. In the absence of dystrophin, muscle cells undergo degeneration and necrosis and eventually are replaced by fibrotic and fatty tissues. It is currently not completely clear how the lack of dystrophin leads to this devastating cascade of events. Several mechanisms have been proposed including contractioninduced sarcolemmal rupture, pathogenic calcium overloading, free radical injury, ischemia, inflammation and aberrant signaling. Recent studies suggest that inducible nitric oxide synthase may represent a common link among several of these proposed mechanisms. iNOS is a calcium-insensitive NOS. Its expression is negligible under normal condition but iNOS is highly up-regulated in inflamed tissues. In dystrophin-deficient mdx mice and DMD patients, iNOS level is markedly elevated in muscle. It is currently not completely clear whether iNOS elevation merely represents an inflammatory signature of muscular dystrophy or it directly contributes to muscle disease in DMD. A recent study by Bellinger et al suggests that iNOS may play an active role in DMD pathogenesis. Bellinger et al observed a disease-associated RyR Butacaine S-nitrosylation in the extensor digitorum longus muscle of mdx mice. Interestingly, they also found a simultaneous increase of iNOS expression and formation of an iNOS-RyR complex. Based on these findings, the authors proposed that iNOS-mediated RyR S-nitrosylation and subsequent intracellular calcium leaking represent important downstream events in dystrophin-deficient muscular dystrophy. Strategies to reduce iNOS-mediated RyR hypernitrosylation and/or RyR calcium channel leaking may ameliorate DMD. In support of this model, Bellinger et al indeed found that pharmacological inhibition of RyR leaking improved voluntary exercise and EDL muscle specific force in mdx mice. In accordance with these findings, here we hypothesize that genetic elimination of iNOS may improve EDL muscle contractility in dystrophin-null mice, presumably via reduced RyR Snitrosylation. Recently, Villalta et al generated iNOS/dystrophin-double null mice by crossing BL6 background iNOS KO mice with C57Bl/10 background mdx mice. Interestingly, the authors focused their analysis on the soleus muscle, a muscle dominated by slow twitch myofibers. They observed reduced myofiber injury and reduced central nucleation but macrophage density and neutrophil number were not altered in the soleus muscle of iNOS-null mdx mice. We examined histopathology and also measured specific forces of the EDL muscle.