Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-DCM that are reversed by LINC complex disruption

The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion and performed comprehensive transcriptomic analyses (bulk, single-nucleus, and spatial) across disease progression.

We identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes. Using mice with inducible, cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, we demonstrated that reducing NE rupture corrected ~50% of misregulated genes and dramatically improved cardiac function and survival in the LMNA-DCM mouse model.