eprintid: 622 rev_number: 14 eprint_status: archive userid: 2 dir: disk0/00/00/06/22 datestamp: 2022-04-13 23:55:16 lastmod: 2023-07-13 23:30:20 status_changed: 2022-04-13 23:55:16 type: article metadata_visibility: show creators_name: Ross, Jacob A. creators_name: Arcos-Villacis, Nathaly creators_name: Battey, Edmund creators_name: Boogerd, Cornelis creators_name: Marhuenda, Emilie creators_name: Hodzic, Didier creators_name: Prin, Fabrice creators_name: Mohun, Tim creators_name: Catibog, Norman creators_name: Tapia Martínez, Olga creators_name: Gerace, Larry creators_name: Iskratsch, Thomas creators_name: Shah, Ajay M. creators_name: Stroud, Matthew J. creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: olga.tapia@uneatlantico.es creators_id: creators_id: creators_id: creators_id: title: Lem2 is essential for cardiac development by maintaining nuclear integrity ispublished: unpub subjects: uneat_bm divisions: uneatlantico_produccion_cientifica full_text_status: public note: PREPRINT 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. date: 2022-02 publication: bioRxiv id_number: doi:10.1101/2022.02.10.477501 refereed: FALSE book_title: Lem2 is essential for cardiac development by maintaining nuclear integrity official_url: http://doi.org/10.1101/2022.02.10.477501 access: open language: en citation: Artículo Materias > Biomedicina Universidad Europea del Atlántico > Investigación > Producción Científica Abierto Inglés 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. metadata Ross, Jacob A.; Arcos-Villacis, Nathaly; Battey, Edmund; Boogerd, Cornelis; Marhuenda, Emilie; Hodzic, Didier; Prin, Fabrice; Mohun, Tim; Catibog, Norman; Tapia Martínez, Olga; Gerace, Larry; Iskratsch, Thomas; Shah, Ajay M. y Stroud, Matthew J. mail SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, olga.tapia@uneatlantico.es, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR (2022) Lem2 is essential for cardiac development by maintaining nuclear integrity. bioRxiv. (Inédito) document_url: http://repositorio.uneatlantico.es/id/eprint/622/1/2022.02.10.477501v1.full.pdf