iNOS expression in dystrophinopathies can be reduced by somatic gene transfer of dystrophin or utrophin

Background: Nitric oxide (NO) is an inorganic gas produced by a family of N O synthase (NOS) proteins. The presence and the distribution of inducible-N OS (NC)S II or iNOS), and NADPH-diaphorase (NADPH-d), a marker for NOS cata lytic activity, were determined in muscle sections from control, DMD, and B MD patients. Materials and Methods: NADPH-d reactivity, iNOS- and nNOS (NOS I)-immunoloc alization were studied in muscles from mdx mice before and after somatic ge ne transfer of dystrophin or utrophin. Results: In control patients, few fibers (<2%) demonstrated focal accumulat ion of iNOS in sarcolemma. In DMD patients, a strong iNOS immunoreactivity was observed in some necrotic muscle fibers as well as in some mononuclear cells, and regenerating muscle fibers had diffusely positive iNOS immunorea ctivity. In DMD patients, NADPH-d reactivity was increased and mainly local ized in regenerating muscle fibers. In mdx mice quadriceps, iNOS expression was mainly observed in regenerating muscle fibers, but not prior to 4 week s postnatal, and was still present 8 weeks after birth. The expression of d ystrophin and the overexpression of utrophin using adenovirus-mediated cons tructs reduced the number of iNOS-positive fibers in mdx quadriceps muscles . The correction of some pathology in mdx by dystrophin expression or utrop hin overexpression was independent of the presence of nNOS. Conclusions: These results suggest that iNOS could play a role in the physi opathology of DMD and that the abnormal expression of iNOS could be correct ed by gene therapy.