ABSTRACT In cirrhosis, hyperammonemia is a consistent abnormality due to impaired hepatic ureagenesis and portosystemic shunting. Sarcopenia or loss of skeletal muscle mass is a major complication of hyperammonemia in cirrhosis and portosystemic shunting. Despite nearly universal recognition of the prevalence and adverse clinical consequences of sarcopenia, there are no effective therapies because the mechanisms of muscle loss in cirrhosis are not well understood. Loss of muscle mass occurs due to dysregulated protein homeostasis or proteostasis with impaired protein synthesis and increased proteolysis by autophagy. Protein homeostasis during cellular stress is achieved by activating an integrated stress response (ISR) in response to eIF2α phosphorylation via the activating transcription factor 4. Ammonia is a cellular stressor that is generated during amino acid catabolism, purine metabolism and synthesis in the gut. We identified a unique cellular stress response in the skeletal muscle that we have termed the hyperammonemic stress response (HASR). During HASR, we observed an increased phosphorylation and activation of the eIF2α kinase and amino acid deficiency sensor, general control nonderepressed 2 (GCN2) that is reversed by L- leucine supplementation. These perturbations resemble an amino acid deficiency response despite increased cellular L-leucine concentrations during hyperammonemia. Interestingly, we also observed that only one of the 3 components of the unfolded protein response (UPR), IRE1α, is activated during HASR. Interestingly, the other 2 limbs of the UPR: PERK, the classical mediator of Endoplasmic Reticulum (ER) stress and ATF6 were not activated during HASR. Unlike the cellular stress responses with eIF2α phosphorylation, the integrated stress response with induction of ATF4 and its targets that support translational recovery were also not observed during HASR. These observations show that HASR shares some characteristics of amino acid deficiency response (without deficiency) and some features of the UPR. Our preliminary and published data suggest a concentration and time dependent initial adaptive that progresses to a maladaptive phase in the skeletal muscle results in sarcopenia. We hypothesized that HASR is activated in response to hyperammonemia and involves a GCN2/mTORC1 axis that represses protein synthesis and induces an adaptive response of increased amino acid uptake and proteostasis control via the amino acid transporter SLC7A5. We also hypothesize that during HASR, only the IRE1α/XBP1s is activated with increased autophagy and mRNA degradation via RIDD (Regulated IRE1α dependent decay). The mechanisms of HASR and interventions that can increase protective adaptations to hyperammonemia in myotubes will be studied in a comprehensive array of cellular and rodent models of hyperammonemia and in the skeletal muscle of human cirrhotics in 3 specific aims. In each aim, a specific molecular therapeutic intervention will be t...