Dystrophin and nNOS double knockout mice maintain dystrophic phenotype

Abstract

Neuronal nitric oxide synthase (nNOS) is anchored to the muscle sarcolemma membrane via the dystrophin glycoprotein complex, nNOS is absent from the sarcolemma of l)uchenne muscular dystrophy (DMD) patients and mdx mice (model for DMl)). We tested the hypothesis that misl0calization or misregulation of nNOS in dystrophic muscle contributes to the disease pathology. To directly assess the role of nNOS in mdz muscle, we generated dystrophin-nNOS double knockout mice by mating nNOS single knockout mice with mdx mice. The double knockout mice are indistinguishable from the rndx mice in terms of dystrophic muscle morphology and sarcolemma membrane damage. These results indicate that the mdx pathology does not directly result from aberrant localization of nNOS. Hence, nNOS absence in mdx and DMD tissue is likely a secondary effect to the loss of dystrophin and does not participate in the disease pathogenesis. K.P.C. is an investigator of the Howard tlughes Medical Institute. R.H.C. is supported by a post-doctorM research fellowship from tile Muscular Dystrophy Association.