Reducing Nuclear Rupture Rescues Gene Expression and Survival in LMNA -DCM

BACKGROUND: Mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C, account for 6% to 8% of all cases of congenital dilated cardiomyopathy. LMNA -related dilated cardiomyopathy is among the most severe forms of dilated cardiomyopathy, with limited treatment options due to an incomplete understanding of its molecular mechanisms. METHODS: We generated an inducible, cardiomyocyte-specific Lmna deletion mouse model (cKO) and conducted comprehensive bulk, single-nucleus, and spatial transcriptomic analyses on left ventricular free wall tissue from cKO and controls lacking the floxed Lmna alleles mice across disease progression. Concurrent cardiomyocyte-specific expression of a dominant-negative KASH domain protein (DN KASH) that disrupts the linker of nucleoskeleton and cytoskeleton complex was used to determine the role of mechanically induced nuclear envelope rupture in altered gene expression. RESULTS: We identified genes misregulated early in disease that were enriched for cytosolic pattern recognition receptor signaling and innate immunity. These transcriptional changes were primarily driven by a subset of disease-specific cardiomyocytes. Spatial and single-nucleus transcriptomics revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to widespread transcriptional dysregulation in cKO hearts. Concurrent disruption of the linker of nucleoskeleton and cytoskeleton complex significantly reduced nuclear envelope rupture, normalized expression of over half the dysregulated genes, and dramatically improved cardiac function and survival in cKO mice. CONCLUSIONS: Our findings support a model in which nuclear envelope rupture in cKO cardiomyocytes triggers cytosolic DNA sensing pathways and maladaptive cell-cell communication with fibroblasts and immune cells, driving inflammation, fibrosis, and cardiac dysfunction. The work presented here points to novel strategies for treating LMNA -dilated cardiomyopathy.