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

Biosci Rep. 2017 Jul 7;37(4):BSR20170707. doi: 10.1042/BSR20170707. Print 2017 Aug 31.

Abstract

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 NaN3 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 NaN3 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.

Keywords: Exon junction complex; cardiomyocytes; hypoxia; metabolic stress; myocardial infarction; myocardium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism*
  • DEAD-box RNA Helicases / metabolism*
  • Myocardial Contraction*
  • Myocytes, Cardiac / metabolism*
  • Protein Transport
  • Rats
  • Stress, Physiological*

Substances

  • eIF4a3 protein, rat
  • DEAD-box RNA Helicases