ABSTRACT Despite the high clinical significance of sarcopenia in alcohol-related liver disease, there are no effective therapies because the mechanisms are not well understood. In the ongoing funding cycle, we identified that kinase-independent dephosphorylation of critical signaling molecules in the skeletal muscle resulted in reduced protein synthesis and increased autophagy mediated proteolysis. Ethanol increased the activity of protein phosphatase 2A (PP2A) that caused targeted inactivation of mTOR and AMPK, critical signaling molecules regulating muscle protein homeostasis (proteostasis). We also observed that ethanol inhibited the lipid- and protein-kinase activities of gamma isoform of phosphoinositide 3 kinase (PI3K), a known inhibitor of PP2A. The downstream signaling responses to ethanol-mediated increased PP2A activity was the simultaneous inhibition both AMPK and mTOR, that have opposing effects on protein synthesis and autophagic proteolysis but the functional consequences were due to impaired mTORC1 signaling responses. Since loss of AMPK occurs in a fed state while mTORC1 is inhibited during fasting, we call the ethanol mediated signaling perturbations to reflect a pseudofed state. Since mTORC1 and AMPK are also responsive to cellular energy deficiency and ethanol causes mitochondrial dysfunction, we evaluated and reported that ethanol impaired mitochondrial function and increased the generation of free radicals in the skeletal muscle that contributed to the signaling perturbations and sarcopenic phenotype. Specifically, complex IV in the electron transport chain was impaired with potential impairment of upstream complexes I and III. Whether ethanol impairs these complexes directly or due to the free radicals generated is not known. Determining the mechanism by which ethanol impairs the specific complexes in the electron transport chain and the functional consequences are also not known. Finally, in the ongoing studies, we are studying the effect of L-leucine on restoring muscle proteostasis and reversing sarcopenia in human patients with alcoholic cirrhosis. However, a large amino acid load increases the nitrogen load and cause hyperammonemia and consequent adverse effects. In preclinical studies in ethanol-treated myotubes and ethanol-fed mice, we noted that -hydroxymethyl butyrate (HMB), a leucine metabolite with anabolic properties, reversed ethanol impaired protein synthesis and reduced mitochondrial oxygen consumption. Based on these preliminary data, we hypothesize that ethanol-induced dysregulation in proteostasis and mitochondrial dysfunction underlies sarcopenia. In the renewal cycle, we propose to dissect the molecular mechanisms of inactivation of PI3K and increased PP2A activity using loss and gain of function studies in preclinical models. We will dissect the specific defects in mitochondrial function using a combination of functional assays and studies to determine the assembly of the electron transport chain comp...