Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment fo r this disease does not exist because the mechanism by which dystrophin def iciency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of th e dystrophin-glycoprotein complex. Recent studies in mice suggest that skel etal muscle-derived nitric oxide may play a key role in the regulation of b lood flow within exercising skeletal muscle by blunting the vasoconstrictor response to cu-adrenergic receptor activation. Here we report that this pr otective mechanism is defective in children with DMD, because the vasoconst rictor response (measured as a decrease in muscle oxygenation) to reflex sy mpathetic activation was not blunted during exercise of the dystrophic musc les. In contrast, this protective mechanism is intact in healthy children a nd those with polymyositis or limb-girdle muscular dystrophy, muscle diseas es that do not result in loss of neuronal nitric oxide synthase. This clini cal investigation suggests that unopposed sympathetic vasoconstriction in e xercising human skeletal muscle may constitute a heretofore unappreciated v ascular mechanism contributing to the pathogenesis of DMD.