Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex in skeletal muscle

Duchenne Muscular Dystrophy (DMD) is a fatal genetic disorder characterized by severe and progressive muscle degeneration, which is caused by mutations in the gene encoding the dystrophin protein. Dystrophin is required for assembly of the dystrophin-glycoprotein complex (DGC) and provides a mechanically strong link between the cytoskeleton and the extracellular matrix. Several DGC proteins 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 the DGC without a link to the cytoskeleton could ameliorate dystrophic pathology. Transgenic mice were generated that express Dp116, a non-muscle isoform of dystrophin that assembles the DGC but lacks actin-binding domains, specifically in skeletal muscle. Expression of Dp116 in skeletal muscles of dystrophin-deficient mice exacerbated muscular dystrophy. Conversely, expression of Dp116 in severely affected mice deficient in both dystrophin and utrophin (a closely related homologue) prevented muscle wasting and increased survival. Dp116 did not restore the signaling molecule neuronal nitric oxide synthase (nNOS) to the DGC, and specific parts of the dystrophin rod domain not found in utrophin were shown to participate in localization of nNOS. However, association of nNOS with the DGC was not required for amelioration of dystrophy. The results suggest that mechanical destabilization, rather than signaling dysfunction, is the primary cause of myofiber necrosis in dystrophin-deficient muscle, but that the severe consequences of the additional loss of utrophin may be due to the loss of homeostatic signaling pathways.

Author dc:creator

• Judge, Luke Milburn

Statement dc:rights

• Copyright is held by the individual authors.

Language dc:language.iso

en_US

Dc Identifier Other

b57285937
77500344
Thesis 56009

OAI identifier oai:identifier

oai:digital.lib.washington.edu:1773/4989