Evaluating the Role of Klotho and Fibroblast Growth Factor 23 in the Pathogenesis of Cardiomyopathy in Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder in which cardiomyopathy has become the leading cause of death. Affected patients develop progressive myocardial fibrosis, chronic inflammation, and left ventricular dysfunction eventually leading to heart failure. Current cardiac management uses adult heart failure therapies targeting the renin-angiotensin-aldosterone system and the sympathetic nervous system , but only modestly delay disease progression. The ability to treat DMD is greatly impaired by our incomplete knowledge of the pathogenic mechanisms underlying cardiomyopathy. We identified Klotho and Fibroblast Growth Factor 23 (FGF23) signaling axis as a potential mediator of cardiac remodeling, however their role in dystrophic hearts has not been defined. This dissertation investigates the contribution of the Klotho and FGF23 signaling axis in the pathogenesis of cardiomyopathy in muscular dystrophy. Our approach to testing this, was to use dystrophin null mdx mice a preclinical mouse model of DMD expressing a Klotho transgene. We also developed a conditional mouse model for fibroblast-specific deletion of FGF23 in mdx mice. We assessed changes in cardiac function and histopathology with steady state progression of disease and using a stressinduced injury model to accelerate cardiac disease progression. Cardiac outcomes were evaluated using echocardiography, histological analysis, and molecular profiling. Our findings demonstrate that Klotho overexpression preserved cardiac function, mitigated fibrosis, and suppressed oxidative stress and damage in mdx mice. Klotho prevented FGF23-mediated cardiac myocyte hypertrophy ex vivo in cells-derived from mdx mice. Furthermore, targeted deletion of FGF23 attenuated dystrophic cardiac dysfunction. Molecular analyses support a pathogenic role for FGF23 in promoting apoptosis, fibrosis, and cardiomyocyte hypertrophy in dystrophic hearts contributing to impaired cardiac function.