Dystrophin deficiency is the cause of
Duchenne muscular dystrophy, but the precise physiological basis for muscle
necrosis remains unclear. To determine whether
dystrophin-deficient muscles are abnormally susceptible to oxidative and
nitric oxide (NO)-driven tissue stress, a hindlimb
ischemia/reperfusion (I/R) model was used. Dystrophic mdx mice exhibited abnormally high levels of lipid peroxidation and
protein nitration, which were preceded by exaggerated NO production during
ischemia. Visualization of NO with the
fluorescent probe 4,5-diaminofluorescein diacetate suggested that excess NO production during
ischemia occurred within a subset of mdx fibers. In mdx muscles only, prior exposure to I/R dramatically increased the level of sarcolemmal damage resulting from stretch-mediated mechanical stress, indicating greatly exacerbated hyperfragility of the dystrophic fiber membrane. Treatment with
NO synthase inhibitors (l-
N(G)-nitroarginine methyl ester hydrochloride or 7-nitroindazol) effectively blocked the synergistic interaction between I/R and mechanical stress-mediated sarcolemmal damage under these conditions. Taken together, our findings provide direct ex-perimental evidence that several prevailing hy-potheses regarding the cause of muscle fiber damage in
dystrophin-deficient muscle can be integrated into a common pathophysiological framework involving interactions between oxidative stress, ab-normal NO regulation, and hyperfragility of the sarcolemma.