Abstract 17200: Altered Nuclear and Cytoskeletal Mechanics and Defective Cell Adhesion in Cardiac Myocytes Carrying the Cardiomyopathy LMNA D192G Mutation

Introduction: Previous investigations suggested that lamin A/C gene (LMNA) mutations, which cause a variety of human diseases including muscular dystrophies and dilated cardiomyopathy, alter the nuclear mechanical properties. Hypothesis: We hypothesized that not only the nucleus, but also the whole-cell biomechanical behavior may be altered in cardiomyocytes with the dilated cardiomyopathy LMNA D192G mutation. Methods: We combined atomic force microscopy (AFM), molecular and cellular biology methodologies to study the biomechanics of the nucleus and whole-cell. Neonatal rat ventricular myocytes (NRVMs) were infected with adenoviral vectors containing either wild type or LMNA D192G. LMNA protein expression was confirmed up to day 6. Nuclear and whole-cell biomechanics were investigated in LMNA D192G, wild type and control NRVMs, . Results: Live-cell AFM force-deformation curves from days 1 through 6 showed that LMNA D192G nuclei displayed higher stiffness and fragility compared to controls with a peak at 72h (P Conclusions: Our study suggests that the cardiomyopathy LMNA D192G mutation has a profound effect on the whole-cell biomechanics in cardiomyocytes, extending beyond the increased nuclear stiffness and fragility, and involving cytoskeletal structural modifications and reduced cell membrane adhesion, changes that can be rescued by wild-type LMNA.