Abstract P2107: Improving Stem Cell Models Of Duchenne Muscular Dystrophy-related Cardiomyopathy By Incorporation Of Physiologic Mechanical Stress
| Autor: | Dominic E Fullenkamp, Alexander B Willis, Jodi L Curtin, Ansel P Amaral, Sloane I Harris, Paul W Burridge, Alexis R Demonbreun, Elizabeth M McNally |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.131.suppl_1.p2107 |
| Popis: | Background: Cardiomyopathy in Duchenne muscular dystrophy (DMD) is a significant driver of disease morbidity and mortality. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer the opportunity to study patient-specific mutations in the dish, however they generally suffer from immaturity. DMD is caused by mutations in the gene DMD , which codes for the protein dystrophin. Dystrophin localizes to the sarcolemma, forming part of a critical transmembrane mechanical and signaling complex that bridges the sarcomere to the extracellular matrix. Disruption of this axis leads to membrane fragility and mechanical stress is a main driver of DMD pathology. New therapies for DMD are in clinical development, including exon skipping, micro-dystrophin gene therapy, CRISPR-based gene editing, and membrane resealants, with some exon skipping strategies receiving FDA approval. The main outcomes of these therapies have been tied to improvement in skeletal muscle function with cardiac efficacy remaining understudied, despite its clear importance for patient outcomes. Results: Equibiaxial strain was employed as a physiologic mechanical stressor to simulate the in vivo mechanism of myocyte injury in an in vitro format using patient-derived DMD iPSC-CMs. By titrating strain, we determined that application of 10% strain for 2 hours robustly differentiates DMD and control iPSC-CMs using the clinically relevant biomarker LDH release as a proxy for membrane damage (control LDH release fold change: no significant change; DMD LDH release fold change: 2.51, p Conclusions: iPSC-CM models can be improved by incorporating physiologic mechanical stress, which is a main driver pathology. This platform is especially useful for evaluating dystrophic cardiomyopathy therapeutics. |
| Databáze: | OpenAIRE |
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