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

摘要

The exon junction complex (EJC) is the main mechanism by which cells select specific mRNAsudfor translation into protein. We hypothesized that the EJC is involved in the regulationudof gene expression during the stress response in cardiac myocytes, with implications forudthe failing heart. In cultured rat neonatal myocytes, we examined the cellular distributionudof two EJC components eukaryotic translation initiation factor 4A isoform 3 (eIF4A3) andudmago nashi homologue (Mago) in response to metabolic stress. There was significant relocalizationudof eIF4A3 and Mago from the nucleus to cytoplasm following 18 h of hypoxia.udTreating myocytes with 50 mM NaN3 for 4 h to mimic the metabolic stress induced by hypoxiaudalso resulted in significant relocalization of eIF4A3 and Mago to the cytoplasm. Toudexamine whether the effects of metabolic stress on the EJC proteins were dependent onudthe metabolic sensor AMP kinase (AMPK), we treated myocytes with 1 μM dorsomorphinud(DM) in combination with NaN3. DM augmented the translocation of Mago and eIF4A3 fromudthe nucleus to the cytoplasm. Knockdown of eIF4A3 resulted in cessation of cell contractilityud96 h post-treatment and a significant reduction in the number of intact sarcomeres.udCell area was significantly reduced by both hypoxia and eIF4A3 knockdown, whilst eIF4A3udknockdown also significantly reduced nuclear size. The reduction in nuclear size is unlikelyudto be related to apoptosis as it was reversed in combination with hypoxia. These data suggestudfor the first time that eIF4A3 and potentially other EJC members play an important roleudin the myocyte stress response, cell contractility and morphology.