Ross, Jacob A. and Arcos-Villacis, Nathaly and Battey, Edmund and Boogerd, Cornelis and Marhuenda, Emilie and Hodzic, Didier and Prin, Fabrice and Mohun, Tim and Catibog, Norman and Tapia Martínez, Olga and Gerace, Larry and Iskratsch, Thomas and Shah, Ajay M. and Stroud, Matthew J. UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, olga.tapia@uneatlantico.es, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED (2022) Lem2 is essential for cardiac development by maintaining nuclear integrity. bioRxiv. (Unpublished)
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2022.02.10.477501v1.full.pdf - Draft Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (4MB) | Preview |
Abstract
Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood. We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation. Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.
| Item Type: | Article |
|---|---|
| Additional Information: | PREPRINT |
| Subjects: | Subjects > Biomedicine |
| Divisions: | Europe University of Atlantic > Research > Scientific Production |
| Depositing User: | Sr Bibliotecario |
| Date Deposited: | 13 Apr 2022 11:53 |
| Last Modified: | 13 Jul 2023 06:58 |
| URI: | http://repositorio.funiber.org/id/eprint/622 |
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