406. The MDX/UTR +/- Mouse Is a Superior Mouse Model for Duchenne Muscular Dystrophy

Abstract

Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease caused by the absence of the dystrophin protein. Dystrophin, the core component of the dystrophin-associated glycoprotein complex, is responsible in stabilizing the sarcolemma during muscle contraction and relaxation. In the absence of dystrophin, muscle becomes fragile and susceptible to damage. This results in progressive muscle degeneration and replacement with fibrotic tissue. The mdx mouse is the most commonly used animal model for DMD. However, it is also considered a poor model because it cannot reproduce the severe dystrophic phenotype seen in patients. Genetic elimination of utrophin, an autosomal homolog of dystrophin, yields a symptomatic double knockout (dko) model. Unfortunately, human patients do not have utrophin deficiency. An utrophin heterozygous mdx (mdx/utrn+/-) mouse would theoretically be a better model should it show more severe muscle dysfunction than the mdx mouse. To test this hypothesis, we systematically examined diaphragm disease in 2-m-old sex-matched mdx and mdx/utm+/-mice. Compared to the mdx mouse, the mdx/utrn+/-mouse displayed more defective histological changes. Importantly, muscle force and passive property were significantly more compromised in the mdx/utrn+/-mouse. Collectively, our data demonstrated for the first time that the mdx/utrn+/-mouse represent a better DMD model at both morphological and physiological levels.