Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex.

ABSTRACT

Duchenne muscular dystrophy (DMD) and limb girdle muscular dystrophy (LGMD) 2C-F result from the loss of dystrophin and the sarcoglycans, respectively. Dystrophin, a cytoskeletal protein, is closely associated with the membrane-bound sarcoglycan complex. Despite this tight biochemical association, the function of dystrophin and the sarcoglycan subunits may differ. The loss of dystrophin in skeletal muscle results in muscle that is highly susceptible to contraction-induced damage, but the skeletal muscle of mice lacking γ- or δ-sarcoglycan are less susceptible. Using mouse models of DMD, LGMD-2C, and LGMD-2F, we demonstrate that isolated cardiac myocytes from mice lacking either γ- or δ-sarcoglycan have normal compliance. In contrast, dystrophin-deficient myocytes display poor passive compliance and are susceptible to terminal contracture following mild passive extensions. Mice deficient in dystrophin and, less so, δ-sarcoglycan have reduced survival during in vivo dobutamine stress testing compared to controls. Catheter-based hemodynamic studies show deficits in both baseline and dobutamine-stimulated cardiac function in all of the dystrophic mice compared to control mice, with dystrophin-deficient mice having the poorest function. In contrast, histopathology showed increased fibrosis in the sarcoglycan-deficient hearts, but not in hearts lacking dystrophin. In summary, this study provides important insights into the unique mechanisms of disease underlying these different models of inherited dystrophic cardiomyopathy and supports a model where dystrophin, but not the sarcoglycans, protects the cardiac myocyte against mechanical damage.