The Functional Role of Dystrophin in the Heart: Implications for Inherited and Non-Inherited Heart Disease.

Abstract

The central focus of this thesis is the pathogenesis of cardiomyopathy caused by loss of dystrophin, and how this may be a unifying mechanism for cardiac dysfunction in inherited and non-inherited heart disease. Dystrophin is a cytoskeletal protein most well known as the defective protein causal for Duchenne muscular dystrophy (DMD), an inherited disease of profound skeletal and cardiac muscle deterioration. The cardiomyopathy of DMD is structurally characterized by progressive ventricular dilation. Previous studies have identified membrane instability as the primary cellular defect in DMD, leading to stiffness and susceptibility to mechanical damage of dystrophin deficient individual cardiac myocytes. I sought to expand on these findings and gain insight into the mechanism by which loss of dystrophin manifests as whole organ ventricular dilation. Unexpectedly, I found that isolated mdx hearts show increased whole-organ compliance. Additionally, I found that large excursions in left ventricular volume of dystrophin deficient hearts were not matched by similar increases in sarcomere length. These findings suggest that loss of dystrophin promotes translation or “slippage” of myocytes which may explain the heightened propensity for pathological dilation observed in DMD patients. Additional experiments in other genetic models of dystrophy suggest that myocyte slippage may be a common mechanism for ventricular dilation in muscular dystrophy. In addition to these studies on inherited dystrophin deficiency, I also carried out studies determining mechanisms for dystrophin deficiency during enterovirus infection. The 2A protease expressed by enteroviruses (2Apro) cleaves dystrophin. Previous studies suggest that truncated dystrophin fragments that can bind β-dystroglycan but not actin cause dystrophy by acting in a dominant negative manner to dystrophin. To determine if the products of dystrophin cleavage by 2Apro behave similarly, I transgenically expressed these proteins in the heart. I found that the C-terminal dystroglycan-binding fragment (CtermDys) caused dystrophic cardiomyopathy and loss of dystrophin from the membrane. These findings are consistent with CtermDys exerting a dominant negative effect on DGC function and suggest a novel mechanism for enteroviral cardiomyopathy. Collectively, the findings of this dissertation provide new knowledge of dystrophin’s physiological role in heart and the effects of dystrophin deficiency on cardiac function.