Document Type

Article

Publication Date

5-8-2024

Comments

This article is the author’s final published version in Science Advances, Volume 10, Issue 19, May 2024, Article number eadh0798.

The published version is available at https://doi.org/10.1126/sciadv.adh0798. Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.

Publication made possible in part by support from the Jefferson Open Access Fund

Abstract

Mutations in the LMNA gene encoding lamins A/C cause an array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis underlying cardiac dysfunction remains elusive. Using a novel conditional deletion model capable of translatome profiling, we observed that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Before cardiac dysfunction, Lmna-deleted cardiomyocytes displayed nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation. Translatome profiling identified MED25 activation, a transcriptional cofactor that regulates Golgi stress. Autophagy is disrupted in the hearts of these mice, which can be recapitulated by disrupting the Golgi. Systemic administration of modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival. These studies support a hypothesis wherein stress responses emanating from the perinuclear space contribute to the LMNA cardiomyopathy development.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Additional Files
Supplementary Materials.pdf (13581 kB)

Language

English

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