End stage cirrhosis and its complications result in 27,000 deaths and 6,500 liver transplants annually in the United States. Reduced skeletal muscle mass or sarcopenia is one of the major complications of portosystemic shunting (PSS) that accompanies cirrhosis. Sarcopenia contributes significantly to the morbidity and mortality of these patients. There are no effective treatment options since the underlying mechanisms are currently unknown and most studies to date have been descriptive. Patients with cirrhosis and PSS as well as animal models have reduced muscle protein synthesis but the molecular mechanisms regulating this process are currently not known. Hyperammonemia is a consistent abnormality in cirrhosis and PSS due to impaired hepatic detoxification of ammonia. Our preliminary data in animal models of hyperammonemia and in muscle cell cultures exposed to ammonia showed an increased expression of myostatin. Myostatin inhibits skeletal muscle protein synthesis and results in lower muscle mass. The mechanism of increased myostatin induced by ammonia is not known. Our preliminary studies have demonstrated NFkB binding sites on the myostatin promoter and NFkB may be an upstream regulator of myostatin during hyperammonemia. In our preliminary studies in myoblast cells, NFkB was increased in response to ammonia and preceded the elevated expression of myostatin. Finally, in both our in vivo studies in PCA rat as well as cell cultures, we observed greater activation of a cellular energy sensor, AMP kinase when myostatin expression was elevated and these alterations were reversed by blocking myostatin in vivo. We therefore hypothesized that hyperammonemia induced increased expression of myostatin inhibits muscle protein synthesis and muscle mass constituting a liver muscle axis. To identify the underlying molecular mechanisms responsible for the reduced muscle protein synthesis with PSS we propose the following aims: 1) Establish that ammonia induced myostatin expression constitutes a liver-muscle axis in vivo, 2) Demonstrate that the mechanism of hyperammonemia mediated upregulation of myostatin expression is NFkB dependent and 3) Establish that the regulation of mTOR by myostatin is independent of Akt and is mediated by AMP kinase in hyperammonemia. Pharmacological, chemical and genetic approaches in animal models and cell culture systems will be used in these studies. The proposed studies are innovative because they will demonstrate the mechanism by which hyperammonemia inhibits muscle protein synthesis and identify a novel regulatory crosstalk between myostatin and mTOR, a critical signaling molecule that regulates protein synthesis. These studies are very significant because they will lay the foundation for understanding the mechanisms of sarcopenia in portosystemic shunting and identify potential therapeutic targets. Furthermore, the results from these studies have the potential to be rapidly translated to clinical application by using pharmacological methods to lower ammonia mediated increased myostatin expression.

Public Health Relevance

Reduced skeletal muscle mass (sarcopenia) is a major complication of cirrhosis with portosystemic shunting and contributes significantly to the morbidity and mortality. There are no effective therapies for this sarcopenia of liver disease. The present proposal uses state of the art methodologies in a broad array of in vivo and in vitro systems to identify the mechanisms of muscle loss in portosystemic shunting. The results from these studies have the potential for rapid clinical translation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Sherker, Averell H
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
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Dasarathy, Srinivasan; Hatzoglou, Maria (2018) Hyperammonemia and proteostasis in cirrhosis. Curr Opin Clin Nutr Metab Care 21:30-36
Horvath, Bela; Allende, Daniela; Xie, Hao et al. (2017) Interobserver Variability in Scoring Liver Biopsies with a Diagnosis of Alcoholic Hepatitis. Alcohol Clin Exp Res 41:1568-1573
Dasarathy, Jaividhya; Varghese, Rony; Feldman, Abram et al. (2017) Patients with Nonalcoholic Fatty Liver Disease Have a Low Response Rate to Vitamin D Supplementation. J Nutr 147:1938-1946
Kumar, Avinash; Davuluri, Gangarao; Silva, Rafaella Nascimento E et al. (2017) Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology 65:2045-2058
Dasarathy, Srinivasan; Mookerjee, Rajeshwar P; Rackayova, Veronika et al. (2017) Ammonia toxicity: from head to toe? Metab Brain Dis 32:529-538
Dasarathy, Srinivasan (2017) Are Exercise Benefits in Nonalcoholic Fatty Liver Disease Due to Increased Autophagy? Exerc Sport Sci Rev 45:125
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 (2016) Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol 32:159-65
Dasarathy, Srinivasan; Dasarathy, Jaividhya; Khiyami, Amer et al. (2016) In Response. J Clin Gastroenterol 50:181

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