Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with duchenne muscular dystrophy

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Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal andcardiacmuscles. Currently, dilated cardiomyopathy due 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 resting Ca<sup>2+</sup>, 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<sup>2+</sup> 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. Our model could be used for themechanistic study ofhumanmuscular dystrophy, aswell as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.

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Lin, B., Li, Y., Han, L., Kaplan, A. D., Ao, Y., Kalra, S., … Yang, L. (2015). Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with duchenne muscular dystrophy. DMM Disease Models and Mechanisms, 8(5), 457–466. https://doi.org/10.1242/dmm.019505

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