The aim of this study was to investigate the role of skeletal muscle in ammonia and glutamine metabolism during chronic hyperammonemia induced by liver insufficiency. The hindquarter ammonia and amino acid fluxes and muscle tissue concentrations were studied in two rat models of chronic liver insufficiency, portacaval shunting and portacaval shunting plus bile-duct ligation, as well as in sham-operated animals, 7 and 14 days after surgery, and in normal, unoperated rats. To reduce nutritional influences, portacaval-shunted rats and sham-operated rats were pair-fed to portacaval shunt biliary obstruction rats. Arterial ammonia levels were elevated in both liver insufficiency groups. In the portacaval shunting plus bile-duct ligation group, arterial glutamine levels were elevated compared with sham-operated controls. No net hind-quarter ammonia uptake was observed in any of the groups, despite hyperammonemia in the chronic liver insufficiency groups. Hindquarter glutamine release was always increased in the liver insufficiency groups compared with sham-operated controls, despite similar muscle glutamine levels in the sham-operated and hyperammonemic groups, suggesting enhanced muscle glutamine synthesis in the latter groups. Muscle ammonia levels were always increased and muscle glutamate decreased in the hyperammonemic groups, probably indicating glutamate consumption by enhanced glutamine synthesis. The increased phenylalanine tissue concentrations and efflux in portacaval shunt/biliary obstruction rats suggest that enhanced net muscle protein breakdown, amino acid catabolism and transamination, rather than ammonia uptake from the blood furnish amino acids and ammonia for enhanced glutamine synthesis. These experiments suggest that nutritional factors are important in explaining altered muscle metabolism during chronic liver insufficiency.