Alcohol impairs insulin and IGF-I stimulation of S6K1 but not 4E-BP1 in skeletal muscle.
The present study determined whether acute alcohol (ethanol; EtOH) intoxication in rats impaired components of the insulin- and IGF-I-signaling pathway in skeletal muscle. Rats were administered EtOH, and 2.5 h thereafter either insulin, IGF-I, or saline was injected and the gastrocnemius removed. EtOH did not alter the total amount or tyrosine phosphorylation of the insulin receptor, IGF-I receptor, insulin receptor substrate (IRS)-1, or protein kinase B (PKB)/Akt under basal or hormone-stimulated conditions. In contrast, the ability of insulin or IGF-I to phosphorylate T389 and T421/S424 on S6K-1 was markedly diminished by EtOH, and these changes were associated with a reduction in the phosphorylation of the ribosomal protein S6. Under basal conditions, EtOH altered the distribution of eukaryotic initiation factor (eIF)4E, as evidenced by a decreased amount of active eIF4E. eIF4G complex, an increased amount of inactive eIF4E. 4E-binding protein (BP)1 complex, and decreased 4E-BP1 phosphorylation. In contrast, EtOH did not impair the ability of either hormone to reverse the changes in eIF4E distribution or 4E-BP1 phosphorylation. Pretreatment with a glucocorticoid receptor antagonist was unable to attenuate either the basal EtOH-induced changes in eIF4E distribution or the impaired ability of IGF-I to stimulate S6K1 and S6 phosphorylation. Hence, acute alcohol intoxication alters selected aspects of translational control under both basal and anabolic hormone-stimulated conditions in skeletal muscle in a glucocorticoid-independent manner.
Kumar
Vinayshree
V
Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.
Frost
Robert A
RA
Lang
Charles H
CH
D000208:Acute Disease; D000435:Alcoholic Intoxication / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014443:Tyrosine / Q000378:metabolism
D002352:Carrier Proteins; D002492:Central Nervous System Depressants; C499526:Eif4ebp1 protein, rat; D039562:Eukaryotic Initiation Factor-4F; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000431:Ethanol; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases