The prevalence and incidence of alcoholic liver disease is increasing. Loss of skeletal muscle mass or sarcopenia is the most frequent complication of alcoholic liver disease and adversely affects survival, quality of life and development of other complications of liver disease. Sarcopenia is more severe and progresses more rapidly in alcoholic than in non-alcoholic patients. This suggests a direct effect of ethanol in addition to other consequences of liver disease in mediating sarcopenia. It is also known that alcohol related muscle loss and myopathy are five times more frequent than liver disease. Despite recognition of the high clinical significance, there are no therapeutic options primarily because the mechanisms of sarcopenia in alcoholic liver disease are not known. Reduced skeletal muscle protein synthesis by alcohol has been described in the past. However, since impaired protein synthesis alone is not enough to cause muscle loss, an increase in protein breakdown is also necessary for the development of sarcopenia in alcoholic liver disease. The ubiquitin-proteasome pathway and autophagy are two well-recognized mechanisms of skeletal muscle protein breakdown. We have previously reported that ethanol increases skeletal muscle mediated autophagy with unaltered or decreased proteasome activity. The goal of the present studies is to determine the molecular mechanisms responsible for ethanol mediated increase in skeletal muscle autophagy, to identify potential therapeutic targets and to perform clinical translational studies. Molecular and metabolic studies in a comprehensive array of models will be used in human subjects with alcoholic cirrhosis, and genetically modified mice and C2C12 muscle cells exposed to alcohol. Our preliminary studies showed that alcohol inhibits activation of mTOR, a known inhibitor of autophagy, and AMPK, that activates autophagy due to dephosphorylation of these counter-regulatory signaling molecules. We also observed that the activity of protein phosphatase 2A, a critical dephosphorylase, increased while the activity of its upstream inhibitor, PI3K? was reduced by alcohol. Finally, reactive oxygen species, generated by mitochondrial and microsomal alcohol metabolism, inhibits PI3K?. We therefore hypothesize that impaired PI3K?-PP2A axis mediates skeletal muscle autophagy in alcoholic liver disease. We will test this hypothesis by 2 specific aims to demonstrate that the mechanism of alcohol mediated impairment of the skeletal muscle PI3K?-PP2A axis is due to ROS generated from alcohol metabolism and increased dephosphorylation impairs downstream canonical mTOR targets with consequent increased autophagy and sarcopenia. Skeletal muscle from genetically modified mice with PI3K? knockout, CYP2E1 knockout, in-vivo electroporation with constitutively active mTOR, murine myotubes exposed to alcohol and patients with alcoholic cirrhosis administered essential amino acids with excess leucine to directly activate mTOR will be used. These studies in a comprehensive array of model systems will lay the foundation for developing novel, mechanism based targeted therapies to reverse sarcopenia in alcoholic liver disease.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Cleveland Clinic Lerner
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