Oral leucine enhances myocardial protein synthesis in rats acutely administered ethanol.
Acute alcohol ingestion induces an inhibition of myocardial protein synthesis by impairing mRNA translation initiation. Elevating plasma leucine (Leu) concentrations via oral gavage stimulates mRNA translation initiation in several tissues, although the effect in heart has not been well defined. The experiments described herein were designed to test the effects of a gavage solution containing Leu on protein synthesis and potential mechanisms important in accelerating mRNA translation initiation in cardiac muscle of rats given ethanol acutely to mimic "binge" dinking. Gavage with Leu stimulated protein synthesis and enhanced the assembly of the active eukaryotic initiation factor (eIF)4G.eIF4E complex. Increased assembly of the active eIF4G.eIF4E complex was associated with a 130% rise in phosphorylation of eIF4G(Ser(1108)) and a decreased assembly ( approximately 30%) of inactive eIF4E-binding protein1 (4EBP1).eIF4E complex in rats-administered ethanol. The reduced assembly of the 4EBP1.eIF4E complex was associated with an increase in phosphorylation of 4EBP1 in the hyperphosphorylated gamma-form following Leu gavage. Phosphorylation of mammalian target of rapamycin on Ser(2448), an upstream regulator of phosphorylation of 4EBP1, was elevated following Leu gavage. Neither the phosphorylation of 70-kDa ribosomal protein S6 kinase on Thr(389) nor eIF4E phosphorylation was increased following Leu gavage under any condition. Leu gavage accelerates myocardial protein synthesis following acute ethanol intoxication by enhancing eIF4G.eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4EBP1 with eIF4E.
Vary
Thomasc
T
Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA. tvary@psu.edu <tvary@psu.edu>
D000284:Administration, Oral; D000818:Animals; D002310:Cardiomyopathy, Alcoholic / Q000188:drug therapy / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D000431:Ethanol; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine