Abstract 557: Combined Loss of Dystrophin and Integrin β1 in Murine Heart Leads to Severe Cardiomyopathy
The dystrophin glycoprotein complex (DGC) links the cytoskeleton and extracellular matrix (ECM) in muscle, maintaining sarcolemma integrity. Transmembrane heterodimeric (αβ) integrins are also cellular adhesion molecules and mechanotransducers, converting mechanical to biochemical stimuli. Integrins have been found to compensate for DGC loss in skeletal muscle (Sk.M). Mdx mice with loss of dystrophin, show destabilization of the entire DGC and display more severe abnormalities in Sk.M. than cardiac M. We hypothesized that ablation of cardiac myocyte integrins would lead to a severe cardiomyopathic phenotype in mdx mice. Mdx mice were crossed to ones with cardiac-specific deletion of β1 integrin (β1KO). In heart, β1KO have reduced:
β1D protein (the muscle-specific integrin, 60% vs. control, P < 0.05, N=6),
integrin α7 protein and
phosphorylated focal adhesion kinase (FAK).
β1KOMDX were viable and showed:
severe necrosis and tissue calcification at 3– 4 months of age,
high mortality in peripartum females; and in nulliparous females and males by 6 months,
cardiac hypertrophy and more severe myocardial fibrosis than the mdx or the β1KO groups alone.
Invasive left ventricular (LV) functional analyses at baseline showed decreased contractility (TABLE⇓) compared to control (Lox/Lox, no Cre), β1KO and mdx. Dobutamine stimulation showed that both β1KO and β1KOMDX groups had blunted responses in contractility and relaxation compared to control (Lox/Lox, no Cre) or mdx groups.
Conclusion: Combined deficiency of dystrophin and integrins in murine cardiac myocytes result in more severe cardiomyopathic changes than reduction of either dystrophin or integrins alone.