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1 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA
2 Serono International, Geneva, Switzerland
* To whom correspondence should be addressed. E-mail: clang{at}psu.edu.
Chronic alcohol consumption decreases the concentration of the anabolic hormone insulin-like growth factor (IGF)-I and this change is associated with an impairment in 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 wks on an alcohol-containing diet, either the IGF-I/IGFBP-3 binary complex (BC) or saline was injected twice daily for three consecutive days; pair-fed time-matched control animals were similarly treated. Three hours after the final injection of the BC, 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, relative to controls, by limiting translational efficiency. BC treatment of alcohol-fed rats increased muscle protein synthesis back to basal control values, but the rate remained lower than that of control rats injected with BC. Assessment of potential mechanisms regulating the increased translation efficiency showed that 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- binding protein-1 or eIF4E. Injection of IGF-I/IGFBP-3 did not overcome the decreased eIF2B activity in muscle of alcohol-fed rats. However, the BC reversed the alcohol-induced increase in IGF binding protein-1 and muscle myostatin, known negative regulators of IGF-I action and muscle mass, respectively. These results indicate that exogenous IGF-I, administered as part of a BC to increase its half-life in the circulation, 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 the myopathy that develops in response to chronic alcohol consumption in rats.
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