Lem2 is essential for cardiac development by maintaining nuclear integrity
Article Subjects > Biomedicine Europe University of Atlantic > Research > Articles and books Abierto Inglés Aims Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope and associated proteins 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 heart remains poorly understood. Methods and results We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue and cellular analyses. High resolution episcopic microscopy was used for 3D reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided physiological assessment of Lem2 iCKO adult mice. We found 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 L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Conclusions 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. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established nuclear envelope and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general. metadata Ross, Jacob A and Arcos-Villacis, Nathaly and Battey, Edmund and Boogerd, Cornelis and Avalos Orellana, Constanza and Marhuenda, Emilie and Swiatlowska, Pamela 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 mail UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, olga.tapia@uneatlantico.es, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED, UNSPECIFIED (2023) Lem2 is essential for cardiac development by maintaining nuclear integrity. Cardiovascular Research. ISSN 0008-6363
Full text not available from this repository.Abstract
Aims Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope and associated proteins 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 heart remains poorly understood. Methods and results We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue and cellular analyses. High resolution episcopic microscopy was used for 3D reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided physiological assessment of Lem2 iCKO adult mice. We found 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 L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Conclusions 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. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established nuclear envelope and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general.
Item Type: | Article |
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Subjects: | Subjects > Biomedicine |
Divisions: | Europe University of Atlantic > Research > Articles and books |
Date Deposited: | 25 Apr 2023 23:30 |
Last Modified: | 21 Oct 2024 23:31 |
URI: | https://repositorio.uneatlantico.es/id/eprint/6866 |
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