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Dis Model Mech. 2015 May;8(5):457-66. doi: 10.1242/dmm.019505. Epub 2015 Mar 19.

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

Author information

1
Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.
2
Center for Cellular and Systems Electrophysiology, Departments of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.
3
Department of Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, UK.
4
Departments of Obstetrics and Gynecology, and Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.
5
Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA lyang@pitt.edu.

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. 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, as well as the elevated levels of resting Ca(2+), mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated 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(2+) 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 disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.

KEYWORDS:

Dilated cardiomyopathy; Duchenne muscular dystrophy; Induced pluripotent stem cells

PMID:
25791035
PMCID:
PMC4415895
DOI:
10.1242/dmm.019505
[Indexed for MEDLINE]
Free PMC Article

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