title: Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy.
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.
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.
authors: Bo
authors: B
authors: Lin
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.
authors: Yang
authors: Y
authors: Li
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.
authors: Lu
authors: L
authors: Han
authors: Center for Cellular and Systems Electrophysiology, Departments of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.
authors: Aaron D
authors: AD
authors: Kaplan
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA.
authors: Ying
authors: Y
authors: Ao
authors: Department of Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, UK.
authors: Spandan
authors: S
authors: Kalra
authors: Departments of Obstetrics and Gynecology, and Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.
authors: Glenna C L
authors: GC
authors: Bett
authors: Center for Cellular and Systems Electrophysiology, Departments of Physiology and Biophysics, SUNY, Buffalo, NY 14214, USA.
authors: Randall L
authors: RL
authors: Rasmusson
authors: Department of Stem Cells, Tissue Engineering & Modelling (STEM), University of Nottingham, Nottingham, NG7 2RD, UK.
authors: Chris
authors: C
authors: Denning
authors: Department of Developmental Biology, University of Pittsburgh School of Medicine, 530 45th Street, 8117 Rangos Research Center, Pittsburgh, PA 15201, USA lyang@pitt.edu.
authors: Lei
authors: L
authors: Yang
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000473:pathology* / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D020442:Poloxamer / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000235:genetics
chemical_list: D020442:Poloxamer; D053148:Caspase 3; D002118:Calcium
keywords: Dilated cardiomyopathy; Duchenne muscular dystrophy; Induced pluripotent stem cells