Dmm019505 457..466

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness inskeletal andcardiacmuscles.Currently, dilatedcardiomyopathydue to cardiac muscle loss is one of the major causes of lethality in 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 cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, aswell as the elevated levels of restingCa,mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondriamediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new diseasemechanism.Ourmodel could be used for themechanistic study ofhumanmusculardystrophy,aswell as futurepreclinical testingofnovel therapeutic compounds for dilated cardiomyopathy in DMD patients.