Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle.
Acute alcohol (EtOH) intoxication impairs skeletal muscle protein synthesis. Although this impairment is not associated with a decrease in the total plasma amino acid concentration, EtOH may blunt the anabolic response to amino acids. To examine this hypothesis, rats were administered EtOH or saline (Sal) and 2.5 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in translational control of protein synthesis. Oral Leu increased muscle protein synthesis by the same magnitude in Sal- and EtOH-treated rats. However, the increase in the latter group was insufficient to overcome the suppressive effect of EtOH, and the rate of synthesis remained lower than that observed in rats from the Sal-Sal group. Leu markedly increased phosphorylation of Thr residues 36, 47, and 70 on 4E-binding protein (BP)1 in muscle from rats not receiving EtOH, and this response was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E. 4E-BP1 to the active eIF4E. eIF4G complex. In EtOH-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E availability were partially abrogated. EtOH also prevented the Leu-induced increase in phosphorylation of eIF4G, the serine/threonine protein kinase S6K1, and the ribosomal protein S6. Moreover, EtOH attenuated the Leu-induced phosphorylation of the mammalian target of rapamycin (mTOR). The ability of EtOH to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor I, or Leu. Finally, although EtOH increased the plasma corticosterone concentration, inhibition of glucocorticoid action by RU-486 was unable to prevent EtOH-induced defects in the ability of Leu to stimulate 4E-BP1, S6K1, and mTOR phosphorylation. Hence, ethanol produces a leucine resistance in skeletal muscle, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR, that is independent of elevations in endogenous glucocorticoids.
Lang
Charles H
CH
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
Frost
Robert A
RA
Deshpande
Nobuko
N
Kumar
Vinayshree
V
Vary
Thomas C
TC
Jefferson
Leonard S
LS
Kimball
Scot R
SR
D000284:Administration, Oral; D000435:Alcoholic Intoxication / Q000378:metabolism; D000818:Animals; D000842:Ankle / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D004351:Drug Resistance; D000431:Ethanol / Q000008:administration & dosage*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000008:administration & dosage*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D000431:Ethanol; D011494:Protein Kinases; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D007930:Leucine