Cardiomyopathy in the dystrophin/utrophin-deficient mouse model of severe muscular dystrophy is characterized by dysregulation of matrix metalloproteinases

Abstract

Cardiomyopathy is a significant component in Duchenne muscular dystrophy. Although mdx mice are deficient in dystrophin, they only develop mild indicators of cardiomyopathy before 1year-of-age, making therapeutic investigations using this model lengthy. In contrast, mdx mice also lacking utrophin (utrn(-/-);mdx) show severely reduced cardiac contractile function and histological indicators of cardiomyopathy by 8-10weeks-of-age. Here we demonstrate that utrn(-/-);mdx mice show a similar pattern of cardiac damage to that in dystrophic patients. Matrix metalloproteinases required for ventricular remodeling during the evolution of heart failure are upregulated in utrn(-/-);mdx mice concurrent with the onset of cardiac pathology by 10weeks-of-age. Matrix metalloproteinase activity is further dysregulated due to reduced levels of endogenous tissue inhibitors and co-localizes with fibroblasts and collagen I-containing scars. utrn(-/-);mdx mice are therefore a very useful model for investigating potential cardiac therapies.