IGF-I activates the eIF4F system in cardiac muscle in vivo.
IGF-I acutely stimulates protein synthesis in cardiac muscle through acceleration of mRNA translation. In the present study, we examined the regulatory signaling pathways and translation protein factors that potentially contribute to the myocardial responsiveness of protein synthesis to IGF-I in vivo. IGF-I was injected IV into rats and 20 min later the hearts were excised and homogenized for assay of regulatory proteins. IGF-I increased assembly of the translationally active eukaryotic initiation factor (eIF)4G.eIF4E complex. The increased assembly of eIF4G.eIF4E was associated with an enhanced eIF4G phosphorylation and increased availability of eIF4E. Increased availability of eIF4E occurred as a consequence of diminished abundance of the inactive 4E-BP1.eIF4E complex following IGF-I. The assembly of the 4E-BP1.eIF4E complex appeared to be decreased through an IGF-I-induced phosphorylation of 4E-BP1. IGF-I also caused an increase in the phosphorylation of S6K1. Activation of the potential upstream regulators of 4E-BP1 and S6K1 phosphorylation via PKB and mTOR was also observed. In contrast, there was no effect of IGF-I on phosphorylation of elongation factor (eFE)2. The results suggest the major impact of IGF-I in cardiac muscle occurred via stimulation of translation initiation rather than elongation. Furthermore, the results are consistent with a role for assembly of active eIF4G.eIF4E complex and activation of S6K1 in mediating the stimulation of mRNA translation initiation by IGF-I through a PKB/mTOR signaling pathway.
Vary
Thomas C
TC
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Pennsylvania 17033, USA. tvary@psu.edu
Lang
Charles H
CH
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; D020652:Peptide Elongation Factor 2; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases