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Although an increase in nitric oxide (NO) in muscle is reported to improve the outcome of deflazacort treatment for mdx mouse muscular dystrophy, the genetic homologue of Duchenne muscular dystrophy (DMD), the impact such treatment on the functional outcomes of the disease, including fiber susceptibility to exercise-induced injury, is not established. Experiments were designed to test whether treatment with deflazacort and L-arginine (a substrate for NO synthase, NOS) would change the extent of fiber injury induced by 24 h of voluntary exercise. The impact of exercise-related injury to induce a secondary regenerative response by muscle was also examined as corroborating evidence of muscle damage. Dystrophic mdx mice were treated for 3 wk with placebo, deflazacort, or deflazacort plus either L-arginine or N(G)-nitro-L-arginine methyl ester (a NOS inhibitor). Deflazacort, especially combined with L-arginine, spared quadriceps muscle from injury-induced regeneration (myf5 expression) compared with placebo treatment, despite an increase in membrane permeability immediately after exercise (assessed by Evans blue dye infiltration). Deflazacort alone prevented the typical progressive loss of function (measured as voluntary distance run over 24 h) that was observed 3 months later in placebo-treated mice. Therefore, combined deflazacort plus L-arginine treatment spared mdx dystrophic limb muscle from exercise-induced damage and the need for regeneration and induced a persistent functional improvement in distance run. Results suggest a potential new treatment option for improving the quality of life for boys with DMD.