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The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes

The exon junction complex (EJC) is the main mechanism by which cells select specific mRNAs for translation into protein. We hypothesized that the EJC is involved in the regulation of gene expression during the stress response in cardiac myocytes, with implications for the failing heart. In cultured...

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Autores principales: Pierrat, Olivier A., Paudyal, Anju, Woodruff, James, Koroleva, Olga, Boateng, Samuel Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434082/
https://www.ncbi.nlm.nih.gov/pubmed/28566540
http://dx.doi.org/10.1042/BSR20170707
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author Pierrat, Olivier A.
Paudyal, Anju
Woodruff, James
Koroleva, Olga
Boateng, Samuel Y.
author_facet Pierrat, Olivier A.
Paudyal, Anju
Woodruff, James
Koroleva, Olga
Boateng, Samuel Y.
author_sort Pierrat, Olivier A.
collection PubMed
description The exon junction complex (EJC) is the main mechanism by which cells select specific mRNAs for translation into protein. We hypothesized that the EJC is involved in the regulation of gene expression during the stress response in cardiac myocytes, with implications for the failing heart. In cultured rat neonatal myocytes, we examined the cellular distribution of two EJC components eukaryotic translation initiation factor 4A isoform 3 (eIF4A3) and mago nashi homologue (Mago) in response to metabolic stress. There was significant relocalization of eIF4A3 and Mago from the nucleus to cytoplasm following 18 h of hypoxia. Treating myocytes with 50 mM NaN(3) for 4 h to mimic the metabolic stress induced by hypoxia also resulted in significant relocalization of eIF4A3 and Mago to the cytoplasm. To examine whether the effects of metabolic stress on the EJC proteins were dependent on the metabolic sensor AMP kinase (AMPK), we treated myocytes with 1 μM dorsomorphin (DM) in combination with NaN(3). DM augmented the translocation of Mago and eIF4A3 from the nucleus to the cytoplasm. Knockdown of eIF4A3 resulted in cessation of cell contractility 96 h post-treatment and a significant reduction in the number of intact sarcomeres. Cell area was significantly reduced by both hypoxia and eIF4A3 knockdown, whilst eIF4A3 knockdown also significantly reduced nuclear size. The reduction in nuclear size is unlikely to be related to apoptosis as it was reversed in combination with hypoxia. These data suggest for the first time that eIF4A3 and potentially other EJC members play an important role in the myocyte stress response, cell contractility and morphology.
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spelling pubmed-64340822019-04-12 The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes Pierrat, Olivier A. Paudyal, Anju Woodruff, James Koroleva, Olga Boateng, Samuel Y. Biosci Rep Research Articles The exon junction complex (EJC) is the main mechanism by which cells select specific mRNAs for translation into protein. We hypothesized that the EJC is involved in the regulation of gene expression during the stress response in cardiac myocytes, with implications for the failing heart. In cultured rat neonatal myocytes, we examined the cellular distribution of two EJC components eukaryotic translation initiation factor 4A isoform 3 (eIF4A3) and mago nashi homologue (Mago) in response to metabolic stress. There was significant relocalization of eIF4A3 and Mago from the nucleus to cytoplasm following 18 h of hypoxia. Treating myocytes with 50 mM NaN(3) for 4 h to mimic the metabolic stress induced by hypoxia also resulted in significant relocalization of eIF4A3 and Mago to the cytoplasm. To examine whether the effects of metabolic stress on the EJC proteins were dependent on the metabolic sensor AMP kinase (AMPK), we treated myocytes with 1 μM dorsomorphin (DM) in combination with NaN(3). DM augmented the translocation of Mago and eIF4A3 from the nucleus to the cytoplasm. Knockdown of eIF4A3 resulted in cessation of cell contractility 96 h post-treatment and a significant reduction in the number of intact sarcomeres. Cell area was significantly reduced by both hypoxia and eIF4A3 knockdown, whilst eIF4A3 knockdown also significantly reduced nuclear size. The reduction in nuclear size is unlikely to be related to apoptosis as it was reversed in combination with hypoxia. These data suggest for the first time that eIF4A3 and potentially other EJC members play an important role in the myocyte stress response, cell contractility and morphology. Portland Press Ltd. 2017-07-07 /pmc/articles/PMC6434082/ /pubmed/28566540 http://dx.doi.org/10.1042/BSR20170707 Text en © 2017 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Pierrat, Olivier A.
Paudyal, Anju
Woodruff, James
Koroleva, Olga
Boateng, Samuel Y.
The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title_full The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title_fullStr The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title_full_unstemmed The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title_short The exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
title_sort exon junction complex senses energetic stress and regulates contractility and cell architecture in cardiac myocytes
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434082/
https://www.ncbi.nlm.nih.gov/pubmed/28566540
http://dx.doi.org/10.1042/BSR20170707
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