SKELETAL MUSCLE-SPECIFIC EXPRESSION OF A UTROPHIN TRANSGENE RESCUES UTROPHIN-DYSTROPHIN DEFICIENT MICE

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting dise ase usually resulting in death of patients by their early twenties'. I n contrast, mice lacking dystrophin (Dmd(mdx)), appear physically norm al despite their underlying muscle pathology(2,3). Mice deficient for both dystrophin and the dystrophin-related protein, utrophin, (Dmd(mdx );Utrn(-/-) mice) die between 6 and 20 weeks of age suffering from sev ere muscle weakness with joint contractures, pronounced growth retarda tion and kyphosis, suggesting that dystrophin and utrophin play comple mentary roles(4,5). The exact cause of death in these mice was not det ermined. Here we show that expression of a truncated utrophin transgen e solely within the skeletal muscle of these mutants prevents prematur e death and the development of any clinical phenotype, In the absence of full-length dystrophin and utrophin, the presence of truncated utro phin also decreases muscle fibre regeneration, relocalizes the dystrop hin protein complex to the sarcolemma and re-establishes a normal expr ession pattern of developmental muscle proteins. These data suggest th at Dmd(mdx);Utrn(-/-) mice succumb to a skeletal muscle defect and tha t their reduced lifespan is not due to cardiac or neurogenic component s, The phenotypic rescue observed demonstrates that the Dmd(mdx);Utrn( -/-) mice are an ideal model for testing gene delivery protocols for t he expression of utrophin or dystrophin in skeletal muscle.