Abstract Thu104: ESCRT III-Driven Repair of Nuclear Rupture Reverses Transcriptional Arrest in Lamin-Related Cardiomyopathy

Localized rupture of the nuclear envelope has been observed in myocardial infarction, neurodegenerative disorders, cancer, and senescence, as well as familial cardiomyopathy caused by Lamin A/C mutations, a critical nuclear envelope structural protein. However, its pathogenic significance remains unclear. We recently reported that cardiomyocyte-specific Lamin A/C knockout mice ( Lmna CKO ) – a model for Lamin A/C-associated cardiomyopathy – develop pervasive nuclear envelope rupture in cardiomyocytes. Here, we show that global transcriptional arrest is a direct consequence of nuclear envelope rupture in Lmna CKO mice. Ruptured nuclei in Lmna CKO cardiomyocytes lost RNA Polymerase II (Pol II), accompanied by a reduction of Ser5-phosphorylated, transcriptionally initiating Pol II. This resulted in global transcriptional arrest with downregulation of sarcomeric and metabolic genes. Surprisingly, 40% of ruptured nuclei eventually restored nuclear compartmentalization, suggesting an endogenous repair mechanism. Indeed, the ESCRT-III membrane remodeling machinery, which mediates mitotic nuclear membrane sealing, accumulated at rupture sites in Lmna CKO cardiomyocytes. Repaired nuclei regained Pol II and resumed transcription, indicating that transcriptional arrest resulted from rupture, not Lamin A/C deficiency itself. Inhibiting ESCRT-III accelerated cardiomyopathy in Lmna CKO mice, suggesting that endogenous rupture repair counteracts disease progression. This study implicates rupture-associated transcriptional arrest in the pathogenesis of Lamin A/C-associated cardiomyopathy and suggests enhancing rupture repair as a potential therapeutic strategy.