Combined Deficiency of Dystrophin and β1 Integrin in the Cardiac Myocyte Causes Myocardial Dysfunction, Fibrosis and Calcification

The dystrophin–glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (αβ) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of β1 integrin (β1KO) to generate β1KO mdx . Unstressed β1KO mdx mice were viable and had normal cardiac function; however, high mortality was seen in peri- and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the β1KO mdx mice compared with control (Lox/Lox, no Cre), β1KO, and mdx . Similarly, adult β1KO mdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix γ-carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in β1KO mdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification.