Author(s): R. H. Crosbie;V. Straub;H. Y. Yun;J. C. Lee;J. A. Rafael;J. S. Chamberlain;V. L. Dawson;T. M. Dawson;K. P. Campbell
Abstract: In skeletal muscle, neuronal nitric oxide synthase (nNOS) is anchored to the sarcolemma via the dystrophin-glycoprotein complex. When dystrophin is absent, as in Duchenne muscular dystrophy patients and in mdx mice, nNOS is mislocalized to the interior of the muscle fiber where it continues to produce nitric oxide. This has led to the hypothesis that 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 evaluated the mice for several features of the dystrophic phenotype, including membrane damage and muscle morphology. Removal of nNOS did not alter the extent of sarcolemma damage, which is a hallmark of the dystrophic phenotype. Furthermore, muscle from nNOS-dystrophin null mice maintain the histological features of mdx pathology. Our results demonstrate that relocalization of nNOS to the cytosol does not contribute significantly to mdx pathogenesis.
Keywords: Animals Cytosol/enzymology Female Intracellular Membranes/enzymology/pathology Male Mice Mice, Inbred C57BL Mice, Inbred mdx Mice, Knockout Mice, Transgenic Muscle, Skeletal/ enzymology/ pathology Muscular Dystrophy, Animal/ enzymology/ pathology Neurons/ enzymology Nitric Oxide Synthase/ genetics Nitric Oxide Synthase Type I