Abstract
Nitrosative stress compromises force generation in Duchenne muscular dystrophy (DMD). Both inducible nitric oxide synthase (iNOS) and delocalized neuronal NOS (nNOS) have been implicated. We recently demonstrated that genetic elimination of nNOS significantly enhanced specific muscle forces of the extensor digitorum longus (EDL) muscle of dystrophin-null mdx4cv mice (Li D et al J. Path. 223:88–98, 2011). To determine the contribution of iNOS, we generated iNOS deficient mdx4cv mice. Genetic elimination of iNOS did not alter muscle histopathology. Further, the EDL muscle of iNOS/dystrophin DKO mice yielded specific twitch and tetanic forces similar to those of mdx4cv mice. Additional studies suggest iNOS ablation did not augment nNOS expression neither did it result in appreciable change of nitrosative stress markers in muscle. Our results suggest that iNOS may play a minor role in mediating nitrosative stress-associated force reduction in DMD.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease affecting approximately 1–3 of every 10,000 newborn boys [1]
Our results suggest that inducible nitric oxide synthase (iNOS) may be less important than it has been suggested in modulating force generation in dystrophindeficient muscle
PCR genotyping revealed the loss of wild type iNOS allele and the presence of iNOS KO allele and mdx4cv mutation in iNOS/Dys DKO mice (Figure 1B) [13]
Summary
Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease affecting approximately 1–3 of every 10,000 newborn boys [1]. Dystrophin is a sub-sarcolemmal structural protein essential for muscle cell membrane integrity and signal transduction. In the absence of dystrophin, muscle cells undergo degeneration and necrosis and eventually are replaced by fibrotic and fatty tissues. It is currently not completely clear how the lack of dystrophin leads to this devastating cascade of events. Several mechanisms have been proposed including contractioninduced sarcolemmal rupture, pathogenic calcium overloading, free radical injury, ischemia, inflammation and aberrant signaling (reviewed in [3,4,5])
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