Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex

Abstract

Duchenne muscular dystrophy is a severe disorder caused by mutations in the dystrophin gene. Dystrophin is required for assembly of the dystrophin-glycoprotein complex and provides a mechanically strong link between the cytoskeleton and the extracellular matrix. Several proteins in the complex also participate in signaling cascades, but the relationship between these signaling and mechanical functions in the development of muscular dystrophy is unclear. To explore the mechanisms of myofiber necrosis in dystrophin-deficient muscle, we tested the hypothesis that restoration of this complex without a link to the cytoskeleton ameliorates dystrophic pathology. Transgenic mice were generated that express Dp116, a non-muscle isoform of dystrophin that assembles the dystrophin-glycoprotein complex, in muscles of dystrophin-deficient mdx(4cv) mice. However, the phenotype of these mice was more severe than in controls. Displacement of utrophin by Dp116 correlated with the severity of dystrophy in different muscle groups. Comparison with other transgenic lines demonstrated that parts of the dystrophin central rod domain were required to localize neuronal nitric oxide synthase to the sarcolemma, but this was not correlated with presence or extent of dystrophy. Our results suggest that mechanical destabilization, rather than signaling dysfunction, is the primary cause of myofiber necrosis in dystrophin-deficient muscle.