It is well established that chronic renal failure is associated with loss of lean body mass. Possible explanations for this problem include an inability to limit essential amino acid oxidation and protein degradation when dietary protein is limited by anorexia or therapeutically. Alternatively, uremia could directly stimulate protein catabolism. In rats, we have uncovered evidence that metabolic acidosis not only blunts the responses to a low-protein diet but also directly stimulates the degradation of muscle protein. In cultured muscle cells as well, acidification of the media stimulates protein degradation. The mechanisms for catabolism involve activation of the ATP-ubiquitin-proteasome-dependent pathway causing muscle protein degradation and stimulation of branched-chain ketoacid dehydrogenase activity causing degradation of branched-chain amino acids. Glucocorticoids are required but are not sufficient for these catabolic responses.