Modeling and Studying Mechanism of Dilated Cardiomyopathy Using Induced Pluripotent Stem Cells Derived From Duchenne Muscular Dystrophy (DMD) Patients

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss, becomes one of the major lethal causes of late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem (iPS) cells. DMD iPS cell-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting calcium, mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondriamediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, we treated DMD iPSC-CMs with a membrane sealant Poloxamer 188, which significantly decreased the resting cytosolic calcium level, repressed CASP3 activation and consequently suppressed apoptosis in DMD iPSC-CMs. Altogether, using DMD patientderived iPSC-CMs, we established an in vitro model to manifest the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential novel disease mechanism. Our study benefits mechanistic study of human muscular dystrophy, as well as the future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.