IGF-I/IGFBP-3 ameliorates alterations in protein synthesis, eIF4E availability, and myostatin in alcohol-fed rats.
Chronic alcohol consumption decreases the concentration of the anabolic hormone IGF-I, and this change is associated with impaired muscle protein synthesis. The present study evaluated the ability of IGF-I complexed with IGF-binding protein (IGFBP)-3 to modulate the alcohol-induced inhibition of muscle protein synthesis in gastrocnemius. After 16 wk on an alcohol-containing diet, either the IGF-I/IGFBP-3 binary complex (BC) or saline was injected two times daily for three consecutive days. After the final injection of BC (3 h), plasma IGF-I concentrations were elevated in alcohol-fed rats to values not different from those of similarly treated control animals. Alcohol feeding decreased the basal rate of muscle protein synthesis by limiting translational efficiency. BC treatment of alcohol-fed rats increased protein synthesis back to basal control values, but the rate remained lower than that of BC-injected control rats. The BC partially reversed the alcohol-induced decrease in the binding of eukaryotic initiation factor (eIF)4E with eIF4G. This change was associated with reversal of the alcohol-induced dephosphorylation of eIF4G but was independent of changes in the phosphorylation of either 4E-BP1 or eIF4E. However, BC reversed the alcohol-induced increase in IGFBP-1 and muscle myostatin, known negative regulators of IGF-I action and muscle mass. Hence, exogenous IGF-I, administered as part of a BC to increase its circulating half-life, can in part reverse the decreased protein synthesis observed in muscle from chronic alcohol-fed rats by stimulating selected components of translation initiation. The data support the role of IGF-I as a mediator of chronic alcohol myopathy in rats.
Lang
Charles H
CH
Department of Cellular & Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. clang@psu.edu
Frost
Robert A
RA
Svanberg
Elisabeth
E
Vary
Thomas C
TC
D000437:Alcoholism / Q000150:complications / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004338:Drug Combinations; D000431:Ethanol / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis / Q000378:metabolism; D018908:Muscle Weakness / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D055435:Myostatin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002492:Central Nervous System Depressants; D004338:Drug Combinations; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D039561:Eukaryotic Initiation Factor-4E; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; C525913:Mstn protein, rat; D009124:Muscle Proteins; D055435:Myostatin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D007334:Insulin-Like Growth Factor I