Cardiomyopathic features associated with muscular dystrophy are independent of dystrophin absence in cardiovasculature

Abstract

The loss of dystrophin results in skeletal muscle degeneration and cardiomyopathy in patients with Duchenne muscular dystrophy. In skeletal muscle, dystrophin strengthens the myofiber membrane by linking the submembranous cytoskeleton and extracellular matrix through its direct interaction with the dystroglycan/sarcoglycan complex. In limb-girdle muscular dystrophy, the loss of the sarcoglycans in cardiovasculature leads to cardiomyopathy. It is unknown whether the absence of dystrophin in cardiomyocytes or cardiovasculature leads to the cardiomyopathy associated with primary dystrophin deficiency. We show here that the cardiomyopathic features of the utrophin/dystrophin-deficient mouse can be prevented by the presence of dystrophin in cardiomyocytes but not in cardiovasculature. Furthermore, restoration of the dystroglycans and sarcoglycans to the cardiomyocyte membrane is not sufficient to prevent cardiomyopathy. These data provide the first evidence that dystrophin plays a mechanical role in cardiomyocytes similar to its role in skeletal muscle. These results indicate that treatment of cardiomyocytes but not cardiovasculature is essential in dystrophinopathies.