Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hepatic branched-chain alpha-keto acid dehydrogenase complex plays an important role in regulating branched-chain amino acid levels. These compounds are essential for protein synthesis but are toxic if present in excess. When dietary protein is deficient, the hepatic enzyme is present in the inactive, phosphorylated state to allow conservation of branched-chain amino acids for protein synthesis. When dietary protein is excessive, the enzyme is in the active, dephosphorylated state to commit the excess branched-chain amino acids to degradation. Inhibition of protein synthesis by cycloheximide, even when the animal is starving for protein, results in activation of the hepatic branched-chain alpha-keto acid dehydrogenase complex to prevent accumulation of branched-chain amino acids. Likewise, the increase in branched-chain amino acids caused by body wasting during starvation and uncontrolled diabetes is blunted by activation of the hepatic branched-chain alpha-keto acid dehydrogenase complex. The activity state of the hepatic branched-chain alpha-keto acid dehydrogenase complex is regulated in the short term by the concentration of branched-chain alpha-keto acids (inhibitors of branched-chain alpha-keto acid dehydrogenase kinase) and in the long term by alteration in the total branched chain alpha-keto acid dehydrogenase kinase activity.
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PMID:Nutritional and hormonal regulation of the activity state of hepatic branched-chain alpha-keto acid dehydrogenase complex. 263 49

Anorexia and/or a protein- and calorie-restricted diet can cause protein wasting by limiting the intake of essential amino acids (EAA) and, hence, protein synthesis. By this mechanism plus the effects of inadequate calories, restricted diets could contribute to the loss of lean body mass of uremic patients. Uremia also impairs the normal metabolic responses that must be activated to preserve body protein, thereby augmenting the adverse effects of anorexia. The responses impaired are those that conserve EAA and protein, which results in catabolism of EAA and muscle protein. An important factor that initiates abnormal adaptive responses in uremia is metabolic acidosis, because acidosis stimulates muscle protein degradation and increases the activity of branched-chain ketoacid dehydrogenase and, hence, the catabolism of branched-chain amino acids (BCAA). The effects of acidosis could be mediated by impaired regulation of intracellular pH and/or an increase in glucocorticoid production. Research directed at identifying the specific proteolytic pathways that are activated by metabolic acidosis has excluded a major role for Ca(2+)-activated or lysosomal proteases and suggests activation of an adenosine triphosphate (ATP)- and ubiquitin-dependent proteolytic pathway. The mechanism of activation of this pathway includes an increase in mRNA for enzymes involved in protein and amino acid catabolism.
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PMID:Mechanisms that cause protein and amino acid catabolism in uremia. 841 35

Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.
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PMID:Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism. 951 6

Metabolic acidosis is an important cause of protein-energy wasting, commonly observed in chronic kidney disease (CKD). This wasting is, in part, a result of the imbalance between protein degradation and synthesis induced by metabolic acidosis. The increase in protein degradation seen with metabolic acidosis is largely secondary to increased activities of the adenosine triphosphate-dependent, ubiquitin-proteasome system and branched-chain ketoacid dehydrogenase. Studies consistently have shown increased protein degradation with lower serum bicarbonate levels and/or arterial pH; however, the evidence for the anti-anabolic effects of metabolic acidosis is less consistent. In contrast to these metabolic studies, many cross-sectional studies have shown a direct relationship between the severity of metabolic acidosis and the adequacy of nutritional status in CKD patients. Moreover, lower serum bicarbonate levels have been associated with better survival in some epidemiologic studies of patients undergoing maintenance hemodialysis. It is likely that these relationships are confounded by the direct association of dietary protein intakes with metabolic acidosis-controlling the survival data for measures of dietary protein intakes, malnutrition, and inflammation shows a rather steep increase in the risk of death with lower serum bicarbonate levels. Two randomized controlled studies have shown that correction of metabolic acidosis is associated with reduction in risk for hospitalization in chronic peritoneal dialysis patients; the studies in maintenance hemodialysis patients have been small and inconsistent. For now, metabolic studies and data from clinical trials lend support to the recommendations made by the Nutrition Workgroup of the Kidney Disease Outcomes Quality Initiative to maintain serum bicarbonate levels of 22 mEq/L or greater in all CKD patients. Limited data suggest that a higher serum bicarbonate level (around 24 mEq/L) may be even more beneficial, particularly in chronic peritoneal dialysis patients.
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PMID:Correction of metabolic acidosis to ameliorate wasting in chronic kidney disease: goals and strategies. 1912 76