Figure 7

Schematic of possible site for alcohol-induced inhibition of muscle protein synthesis. This paradigm illustrates the central role served by mTOR (mammalian target of rapamycin) at integrating the independent anabolic signals generated by IGF (insulin-like growth factor-I and the amino acid leucine. mTOR is present in a multimeric protein complex termed mTORC1 which consists of itself, raptor, PRAS40 (proline-rich Akt substrate) and GβL (G protein β-subunit-like protein/mLST8). In addition, a second protein complex exists (mTORC2) consisting of mTOR, GβL, rictor, and mSin1 (mammalian stress-activated protein kinase-interacting protein) and this complex is not shown because it does not appear to directly modulate protein synthesis. mTORC1 has kinase activity which phosphorylates both S6K (ribosomal protein S6 kinase)-1 and 4E-BP1 [eukarytoic initiation factor (eIF) 4E-binding protein-1]. The phosphorylation of 4E-BP1 results in the redistribution of eIF4E from an inactive eIF4E-4EBP1 complex to the active eIF4E-eIF4G complex which, along with other proteins, forms the functional eIF4F complex and stimulates mRNA translation. Present data indicates acute alcohol intoxication increases the association of mTOR and raptor suggesting a "closed" inhibitory confirmation which is consistent with the alcohol-induced decrease in 4E-BP1 and S6K1 phosphorylation. Other reports [6] indicate alcohol does not alter phosphorylation of the IGF-I receptor or protein kinase B (PKB; aka Akt), or the formation of the tuberous sclerosis complex (TSC)-1/TSC-2. Although several possible mechanisms have been reported [51, 52], the signal transduction pathway used by leucine to stimulate protein synthesis in skeletal muscle is poorly defined but is independent of PKB activation. Solid lines with arrow heads represent stimulation, whereas lines terminating in a perpendicular line represent inhibition. Numerous proteins and cofactors have been omitted from the diagram to simplify and improve clarity.