Functional muscle ischemia in Duchenne and Becker muscular dystrophy

Abstract

Duchenne and Becker muscular dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSμ) which binds spectrin-like repeats within dystrophin's rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSμ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSμ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD.

Keywords: Duchenne muscular dystrophy; exercise; functional sympatholysis; neuronal nitric oxide synthase; sympathetic vasoconstriction.

Figure 1

Left panel, in healthy muscle, nNOSμ is localized to the sarcolemma by association with the rod domain of dystrophin and the PDZ domain of α-syntrophin (syn). During muscle contraction, some of the nNOSμ-derived nitric oxide (NO) diffuses to the nearby microvessels where it increases cGMP and attenuates norepinephrine (NE)-mediated vasoconstriction. This NO-mediated functional sympatholysis optimizes blood flow in the working muscles. Right panel, in dystrophic muscle, nNOSμ is reduced in amount and mislocalized from the sarcolemma to the cytosol. Less NO is generated during muscle contraction, resulting in unrestrained sympathetic vasoconstriction and transient functional muscle ischemia, which may exacerbate injury of the diseased muscle fibers. Genetic and pharmacologic interventions targeting different aspects of nNOSμ-NO signaling that alleviate functional muscle ischemia in preclinical studies are shown. sGC, soluble guanylyl cyclase; DG, dystroglycan; PDE, phosphodiesterase.