SRP341427 PRJNA771372 GSE185923 Age-dependent Lamin remodeling induces cardiac dysfunction via dysregulation of cardiac transcriptional programs [ATAC-Seq] As we age, structural changes contribute to progressive decline in organ function, which in the heart acts through poorly characterized mechanisms. Utilizing the rapidly aging fruit fly model with its significant homology to the human cardiac proteome, we found that cardiomyocytes exhibit progressive loss of Lamin C (mammalian Lamin A/C homologue) with age. Unlike other tissues and laminopathies, we observe decreasing nuclear size, while nuclear stiffness increases. Premature genetic reduction of Lamin C phenocopies aging's effects on the nucleus, and subsequently decreases heart contractility and sarcomere organization. Surprisingly, Lamin C reduction downregulates myogenic transcription factors and cytoskeletal regulators, possibly via reduced chromatin accessibility. Subsequently, we find an adult-specific role for cardiac transcription factors and show that maintenance of Lamin C sustains their expression and prevents age-dependent cardiac decline. Our findings are conserved in aged non-human primates and mice, demonstrating age-dependent nuclear remodeling is a major mechanism contributing to cardiac dysfunction. Overall design: Bulk ATAC-Sequencing of Drosophila melanogaster isolated hearts, conducted for control flies, w1118, at 1 week of age (n = 3) and 5 weeks of age (n = 3); Hand-Gal4 x attp2 control flies (n = 4) and Hand-Gal4 x LamC RNAi flies (n = 3) at 1 week of age; and Hand-Gal4 x attp40 control flies (n = 3) and Hand-Gal4 x LamB RNAi flies (n = 4) at 1 week of age. The purpose of sequencing was to identify differentially accessible regions that are common between aging and Lamin C RNAi expressing flies, and aging and Lamin B RNAi expressing flies. GSE185923 parent_bioproject PRJNA771560