Loss of lean body mass occurs frequently in patients with acute or chronic renal failure, but the mechanism(s) causing this abnormality are unknown. Using animal models of experimental uremia, it was found that excess lactate formation in muscle is directly related to the rate of protein breakdown. This suggests that abnormal energy metabolism may be one mechanism for protein wasting. A second mechanism involves metabolic acidosis. Metabolic acidosis activates the catabolism of protein and amino acids in muscle of uremic rats independently of azotemia. Defects in sodium transport by Na,K-ATPase and the Na/K/Cl cotransport system suggest that intracellular ions including hydrogen may be abnormal. If this were the case, uremia would increase the susceptibility to the catabolic effect of metabolic acidosis.