Blocking eukaryotic initiation factor 4F complex formation does not inhibit the mTORC1-dependent activation of protein synthesis in cardiomyocytes

Brandon P H Huang, Yanni Wang, Xuemin Wang, Zhuren Wang, Christopher G. Proud

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Activation of the mammalian target of rapamycin complex 1 (mTORC1) causes the dissociation of eukaryotic initiation factor 4E complex (eIF4E)-binding protein 1 (4E-BP1) from eIF4E, leading to increased eIF4F complex formation. mTORC1 positively regulates protein synthesis and is implicated in several diseases including cardiac hypertrophy, a potentially fatal disorder involving increased cardiomyocyte size. The importance of 4E-BP1 in mTORC1-regu- lated protein synthesis was investigated by overexpressing 4E-BP1, which blocks eIF4F formation in isolated primary cardiomyocytes without affecting other targets for mTORC1 signaling. Interestingly, blocking eIF4F formation did not impair the degree of activation of overall protein synthesis by the hypertrophic agent phenylephrine (PE), which, furthermore, remained dependent on mTORC1. Overex- pressing 4E-BP1 also only had a small effect on PE-induced cardio- myocyte growth. Overexpressing 4E-BP1 did diminish the PE-stim- ulated synthesis of luciferase encoded by structured mRNAs, confirming that such mRNAs do require eIF4F for their translation in cardiomyocytes. These data imply that the substantial inhibition of cardiomyocyte protein synthesis and growth caused by inhibiting mTORC1 cannot be attributed to the activation of 4E-BP1 or loss of eIF4F complexes. Our data indicate that increased eIF4F formation plays, at most, only a minor role in the mTORC1-dependent activation of overall protein synthesis in these primary cells but is required for the translation of structured mRNAs. Therefore, other mTORC1 targets are more important in the inhibition by rapamycin of the rapid activation of protein synthesis and of cell growth.

Original languageEnglish
Pages (from-to)H505-H514
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number2
DOIs
Publication statusPublished or Issued - Feb 2009

Keywords

  • Cardiac hypertrophy
  • Eukaryotic initiation factor 4E-binding protein 1
  • Mitochondrial ribonucleic acid translation
  • Rapamycin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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