Nearly two thirds of adult Americans drink alcohol in varying amounts. The best known clinical consequence of excess alcohol use is the development of alcoholic liver disease. However, reduction in muscle mass and function are a consequence of both alcoholic liver disease as well as a direct effect of alcohol on the skeletal muscle. Loss of skeletal muscle mass or sarcopenia is a major component of alcoholic liver disease and adversely affects survival, quality of life and development of other complications of liver disease. Despite recognition that alcohol related muscle loss and myopathy are five times more frequent than liver disease, there are no therapeutic options to prevent or reverse this process. One of the potential mechanisms responsible for sarcopenia in alcoholic liver disease is the reduction in skeletal muscle protein synthesis. However, impaired protein synthesis alone is not enough and an increase in protein breakdown is necessary for loss of muscle mass to occur. Protein breakdown in the skeletal muscle occurs either in the proteasome or by autophagy, a process by which modified and toxic proteins and damaged organelles are broken down and the products recycled. We have shown that alcohol does not alter proteasome activity but increases autophagy in skeletal muscle. The present studies aim towards understanding the mechanisms responsible for increased autophagy and its pathophysiological role in alcoholic liver disease. A comprehensive approach will be used with studies in human subjects with varying severity of alcoholic liver disease, mice fed ethanol and C2C12 muscle cells exposed to alcohol. Alcohol is metabolized to acetaldehyde that in combination with malondialdehyde, generated by lipid peroxidation in response to alcohol, modifies proteins that are rich in lysine. Muscle proteins are rich in lysine, they are likely to undergo this modification (adducts). These proteins need to be degraded since they are cytotoxic. Since the proteasome pathway is not activated, while autophagy is, we hypothesize that alcohol induces skeletal muscle autophagy to degrade these modified proteins. We also observed that mTOR, a critical inhibitor of mTOR is inhibited while AMPK, that induces autophagy is unaltered by alcohol in the muscle. This was accompanied by activation of protein phosphatase 2A (PP2A) that inactivates mTOR. The proposed studies will permit us to identify this novel AMPK independent, PI3K-PP2A dependent activation of autophagy in the muscle. Identifying the mechanism of increased autophagy will permit identification of potential novel therapeutic targets for sarcopenia of alcoholic liver disease. We will examine this hypothesis by 2 specific aims to demonstrate the formation of the protein adducts in the muscle that are degraded by autophagy via novel signaling pathway in alcoholic liver disease. A comprehensive array of models including muscle tissue from patients with alcoholic liver disease, mice fed ethanol and muscle cells exposed to ethanol will be used for these studies that will lay the foundation for more detailed mechanistic studies and new therapies to reverse sarcopenia in these patients.
Loss of muscle mass is widely prevalent in patients with alcoholic liver disease of varying severity and is an independent predictor of poor outcome in these patients. Even though impaired muscle protein synthesis is a consistent abnormality in these patients, for loss of muscle mass to occur, protein breakdown is necessary. Our preliminary studies have suggested that alcohol induces muscle autophagy and we will identify a novel autophagy mediated mechanism of muscle loss by alcohol.
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|Dasarathy, Srinivasan (2017) Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. J Cachexia Sarcopenia Muscle 8:864-869|
|Dasarathy, Jaividhya; McCullough, Arthur J; Dasarathy, Srinivasan (2017) Sarcopenia in Alcoholic Liver Disease: Clinical and Molecular Advances. Alcohol Clin Exp Res 41:1419-1431|
|Dasarathy, Srinivasan; Brown, J Mark (2017) Alcoholic Liver Disease on the Rise: Interorgan Cross Talk Driving Liver Injury. Alcohol Clin Exp Res 41:880-882|
|Dasarathy, Srinivasan (2017) Are Exercise Benefits in Nonalcoholic Fatty Liver Disease Due to Increased Autophagy? Exerc Sport Sci Rev 45:125|
|Dasarathy, Srinivasan; Merli, Manuela (2016) Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol 65:1232-1244|
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|Dasarathy, Srinivasan (2016) Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol 32:159-65|
|Dasarathy, Srinivasan (2016) Nutrition and Alcoholic Liver Disease: Effects of Alcoholism on Nutrition, Effects of Nutrition on Alcoholic Liver Disease, and Nutritional Therapies for Alcoholic Liver Disease. Clin Liver Dis 20:535-50|
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