Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy

Author:

Sikder Kunal1ORCID,Phillips Elizabeth1ORCID,Zhong Zhijiu2ORCID,Wang Nadan1ORCID,Saunders Jasmine1ORCID,Mothy David1ORCID,Kossenkov Andrew3ORCID,Schneider Timothy4ORCID,Nichtova Zuzana4ORCID,Csordas Gyorgy4ORCID,Margulies Kenneth B.5ORCID,Choi Jason C.1ORCID

Affiliation:

1. Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia PA, USA.

2. Translational Research and Pathology, Thomas Jefferson University, Philadelphia, PA, USA.

3. Bioinformatics Facility, The Wistar Institute Cancer Center, Philadelphia, PA, USA.

4. Mitocare, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.

5. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

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