MDX MUSCLE PATHOLOGY IS INDEPENDENT OF NNOS PERTURBATION

In skeletal muscle, neuronal nitric oxide synthase (nNOS) is anchored to the sarcolemma via the dystrophin-glycoprotein complex. When dystro phin is absent, as in Duchenne muscular dystrophy patients and in mdx mice, nNOS is mislocalized to the interior of the muscle fiber where i t continues to produce nitric oxide. This has led to the hypothesis th at free radical toxicity from mislocalized nNOS may contribute to mdx muscle pathology. To test this hypothesis directly, we generated mice devoid of both nNOS and dystrophin. Overall, the nNOS-dystrophin null mice maintained the dystrophic characteristics of mdx mice. We evaluat ed the mice for several features of the dystrophic phenotype, includin g membrane damage and muscle morphology. Removal of nNOS did not alter the extent of sarcolemma damage, which is a hallmark of the dystrophi c phenotype. Furthermore, muscle from nNOS-dystrophin null mice mainta in the histological features of mdx pathology. Our results demonstrate that relocalization of nNOS to the cytosol does not contribute signif icantly to mdx pathogenesis.