Human Molecular Genetics, Vol 7, 823-829, Copyright © 1998 by Oxford University Press
RH Crosbie, V Straub, HY Yun, JC Lee, JA Rafael, JS Chamberlain, VL Dawson, TM Dawson and KP Campbell
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.
ARTICLES
mdx muscle pathology is independent of nNOS perturbation
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
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