Significance: Loss of skeletal muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects the outcome of these patients. There are no established therapies to prevent or reverse sarcopenia because the mechanisms are not known. We show that the expression of myostatin, a negative regulator of skeletal muscle mass, is increased in the cirrhotic muscle and is mediated by increased ammonia concentration. Skeletal muscle ammonia concentrations are significantly increased in cirrhosis, resulting in activation of the transcription factor NF-κB, which in turn increases the expression of myostatin. Given the high prevalence of cirrhosis, these studies are of broad general interest because ammonia-lowering strategies, NF-κB antagonists, and myostatin blocker are potential therapies to reverse sarcopenia of cirrhosis.