A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice

Dystrophin-deficient muscles experience large reductions in expression of n itric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an anti inflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophi c muscle exacerbates muscle inflammation and fiber damage by inflammatory c ells. Analysis of transgenic mdx mice that were null mutants for dystrophin , but expressed normal levels of NO in muscle, showed that the normalizatio n of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevente d the majority of muscle membrane injury that is detectable in vivo, and re sulted in large decreases in serum creatine kinase concentrations. Furtherm ore, our data show that mdx muscle macrophages are cytolytic at concentrati ons that occur in dystrophic, NOS-deficient muscle, but are not cytolytic a t concentrations that occur in dystrophic mice that express the NOS transge ne in muscle. Finally, our data show that antibody depletions of macrophage s from mdx mice cause significant reductions in muscle membrane injury. Tog ether, these findings indicate that macrophages promote injury of dystrophi n-deficient muscle, and the loss of normal levels of NO production by dystr ophic muscle exacerbates inflammation and membrane injury in muscular dystr ophy.