In Person Special Seminar: Connexin 43: A New Player in Duchenne Muscular Dystrophy and Associated Cardiomyopathy
Diego Fraidenraich, Ph.D., FAHA
Associate Professor
Cell Biology and Molecular Medicine
New Jersey Medical School
Rutgers University
In Person Seminar: Connexin 43: A New Player in Duchenne Muscular Dystrophy and Associated Cardiomyopathy
Date: Jan. 5, 2023
Time: 11 a.m.
Location: Room R3012, 2 Riverside Circle
About this Seminar
Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, Dr. Fraidenraich and his team identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. The team hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, they generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.
You May Also Be Interested In...
-
Home ItemClinical Applications of Cancer Genetics , home
Nov. 21, 2024, 5:30 p.m. (Reception at 5 p.m.) | Luis Diaz, Jr., M.D., Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center; Member, National Academy of Medicine | Maury Strauss Distinguished Public Lecture
-
Home ItemA Ribocentric View of Muscle Proteostasis in Health and Disease: Novel Mechanisms Potential Therapeutic Opportunities , home
Nov. 22, 2024, 11:00 a.m. | Gustavo A. Nader, Ph.D., FAPS, Professor, College of Health and Human Development; Chair, Molecular, Cellular, and Integrative Physiology; Huck Institutes of the Life Sciences; The Pennsylvania State University | Co-Sponsored by the Fralin Biomedical Research Institute Center for Exercise Medicine Research
-
Home ItemHuman Laboratory Evaluation of Cannabis Products , home
Dec. 13, 2024, 11:00 a.m. | Ryan Vandrey, Ph.D., Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine | Co-Sponsored by the Fralin Biomedical Research Institute Center for Health Behaviors Research and the Addiction Recovery Research Center
-
Home ItemMechanics of Convective Cell Motion , home
Jan. 10, 2025, 11:00 a.m. | Michael Murrell, Ph.D., Associate Professor, Department of Biomedical Engineering and Physics, Yale University | Co-Sponsored by the Fralin Biomedical Research Institute Cancer Research Center – Roanoke
-
Home ItemThe Role of Pericytes in Pulmonary Vascular Diseases , home
Jan. 17, 2025, 11:00 a.m. | Vinicio de Jesus Perez, M.D., FCCP, FAHA, Assistant Professor, Wall Center Adult PH Clinic Division of Pulmonary and Critical Care Medicine, Stanford School of Medicine | Co-Sponsored by the Fralin Biomedical Research Institute Center for Vascular and Heart Research
-
Home ItemRethinking Human Health with AI: Solving Old Mysteries with Modern Tools , home
Jan. 23, 2025, 5:30 p.m. (Reception at 5 p.m.) | Regina Barzilay, Ph.D., School of Engineering Distinguished Professor for AI and Health; AI Faculty Lead, Jameel Clinic; MIT Computer Science & Artificial Intelligence Lab; MacArthur Fellow; Member, National Academy of Engineering, American Academy of Arts and Sciences, and the National Academy of Medicine | Maury Strauss Distinguished Public Lecture