Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice

Abstract

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease usually resulting in death of patients by their early twenties¹. In contrast, mice lacking dystrophin (Dmd^mdx), appear physically normal despite their underlying muscle pathology^2,3. Mice deficient for both dystrophin and the dystrophin-related protein, utrophin, (Dmd^mdx;Utm^−/− mice) die between 6 and 20 weeks of age suffering from severe muscle weakness with joint contractures, pronounced growth retardation and kyphosis, suggesting that dystrophin and utrophin play complementary roles^4,5. The exact cause of death in these mice was not determined. Here we show that expression of a truncated utrophin transgene solely within the skeletal muscle of these mutants prevents premature death and the development of any clinical phenotype. In the absence of full-length dystrophin and utrophin, the presence of truncated utrophin also decreases muscle fibre regeneration, relocalizes the dystrophin protein complex to the sarcolemma and re-establishes a normal expression pattern of developmental muscle proteins. These data suggest that Dmd^mdx;Utrn^−/− mice succumb to a skeletal muscle defect and that their reduced lifespan is not due to cardiac or neurogenic components. The phenotypic rescue observed demonstrates that the Dmd^mdx;Utm^−/− mice are an ideal model for testing gene delivery protocols for the expression of utrophin or dystrophin in skeletal muscle.