Myocardial dystrophin-deficiency and its impact on metabolic and nutrient signaling pathways

Defects in the cytoskeletal protein dystrophin have been implicated in the pathogenesis of both genetic and acquired forms of cardiomyopathies. In Duchenne muscular dystrophy (DMD), dystrophin-deficiency results in dilated cardiomyopathy, which represents a major cause of mortality in patients with DMD. So far, the role of dystrophin in the heart remains unclear. A better understanding of the mechanisms by which abnormalities in dystrophin integrity induce cardiac dysfunction appears warranted for the effective management and therapy of DMD and other dystrophin-related cardiomyopathies. While gene therapy and the recently documented cardioprotective effects of a membrane sealant in DMD offer new promising therapeutic avenues, the feasibility of these interventions remains to be demonstrated.This project was aimed at better defining the role of dystrophin in the heart. Specifically, it tested the hypothesis that dystrophin plays a crucial role in regulation of cardiac energy metabolism. This hypothesis was formulated on the following basis. First, increasing evidence indicates that metabolic perturbations occur early in the progression of several types of cardiomyopathies, and contribute to disease progression. Second, dystrophin-deficient hearts display perturbations in calcium handling and nitric oxide (NO) signaling, two factors that play a crucial role in the concerted regulation of energy substrate metabolism and contractile function. Finally, pathways that are central to substrate oxidation, such as the mitochondrial citric acid cycle, have been shown to be dependent on cytoskeletal organization.Given the availability of a mouse model for dystrophin deficiency, namely the mdx mouse, our first objective was to setup an experimental methodology allowing dynamic measurements of cardiac substrate energy metabolism using ex vivo perfusions in the working mode and a carbon 13-labeling strategy. We then used this study model to conduct a detailed functional and metabolic phenotyping of the dystrophin-deficient mdx mouse heart at an age, during which no major histological or echocardiographic abnormalities were reported. Our findings highlight the presence of early "sub-clinical" alterations in the energy substrate metabolism of the dystrophin-deficient heart, which could play a role in the subsequent progression to overt myocardial dysfunction and cardiomyocyte damage. Moreover, the pattern of metabolic alterations was suggestive of an altered NO/cGMP pathway. Therefore, the final aim of this thesis project was to evaluate the potential benefits of an intervention that targets this pathway. We show that pharmacological enhancement of the NO/cGMP pathway in the dystrophy-deficient heart mitigates cardiac remodeling and improves the resistance of cardiomyocytes to mechanical injury. This study provides basis for a therapy that could potentially improve cardiac function in patients suffering from Duchenne and Becker muscular dystrophy