Abstract 15352: Age-associated Nuclear Remodeling May Contribute to Cardiac Dysfunction

Abstract

Introduction: Cardiac performance depends on proper function of the extracellular matrix, cytoskeleton and nucleus to regulate systolic contraction and diastolic relaxation. As we age, the mechanical properties of these structures change, but their influence on tissue-level function is unclear. Nuclear Lamins (Lam), intermediate filaments that underly the nuclear envelope, change in expression and localization with age, leading to irregularly shaped nuclei. Mutations in LamA/C can cause premature aging and cardiomyopathy but whether Lamin changes with age contribute to cardiac dysfunction is unknown. Hence, we hypothesize that age-associated LamA/C reduction remodels nuclear shape, force propagation, and gene accessibility to reduce cardiac function. Methods: We profiled nuclear morphology and protein expression in hearts from two wildtype Drosophila melanogaster strains for up to 5 weeks, when median survival is less than 50%. We performed live imaging to assess heart performance in wildtype flies and flies with Lamin knock-down using the Gal4-UAS system. To profile chromatin accessibility changes we use an ATAC-seq protocol that we optimized for frozen heart nuclei. Results: Cardiomyocyte nuclei become smaller and more circular with age in contrast to skeletal nuclei across w 1118 and yw wildtype fly strains. Expression of both LamB and LamC ( Drosophila LamA/C) decrease with age and differentially regulate nucleus size and circularity. LamC knockdown, but not LamB, induces contractile dysfunction, measured by fractional shortening, at 1-week, and shortens lifespan. LamB and LamC knockdown also mimicked DNA decondensation observed in aged wildtype flies, suggesting that reduced DNA packaging could result from fewer contacts with the nuclear lamina. Thus, we developed a novel ATAC-seq pipeline that will identify how age-related nuclear architecture may influence the epigenome and contribute to pathogenic heart remodeling. Conclusions: Cardiomyocyte nuclei decrease in size and increase in circularity upon aging as a result of diminished Lamin expression. Loss of Lamin expression induces cardiac dysfunction. Our future work aims to elucidate the mechanism by which nuclear aging contributes to age-related cardiac dysfunction.