Journal
DISEASE MODELS & MECHANISMS
Volume 8, Issue 5, Pages 457-466Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.019505
Keywords
Dilated cardiomyopathy; Duchenne muscular dystrophy; Induced pluripotent stem cells
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Funding
- University of Pittsburgh
- American Heart Association (AHA) [11SDG5580002]
- National Institutes of Health (NIH) [1DP2HL127727-01, HL062465]
- National Heart and Lung Institute [HL09363l]
- Medical Research Council
- Heart Research UK
- British Heart Foundation
- National Centre for the Replacement, Refinement and Reduction of Animals in Research
- BBSRC [BB/E006159/1] Funding Source: UKRI
- MRC [G0801098, G113/30] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E006159/1] Funding Source: researchfish
- British Heart Foundation [PG/14/59/31000, PG/09/027/27141] Funding Source: researchfish
- Medical Research Council [G113/30, G0801098] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/C013202/1, NC/K000225/1, NC/C013105/1] Funding Source: researchfish
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Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiacmuscles. 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 Ca2+, 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 Ca2+ 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.
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