Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malnutrition and a loss of lean body mass frequently complicate chronic renal failure. Muscle wasting in uremia is caused by increased protein degradation, decreased protein synthesis and increased branched-chain amino acid oxidation. Acidosis and glucocorticoids are pivotal in these pathophysiologic aberrations. When the acidosis of chronic renal failure is corrected by feeding bicarbonate, protein degradation and amino acid oxidation normalize. Likewise, if patients and animals with normal renal function are made acidotic, protein degradation and amino acid oxidation increase. In adrenalectomized, acidotic rats, proteolysis increases only when they are supplemented with physiologic concentrations of glucocorticoids, suggesting that glucocorticoids are necessary for increased proteolysis. Acidosis stimulates the ATP-dependent proteolytic process involving ubiquitin and the 26S proteasome. Thus, acidosis evokes a glucocorticoid-dependent catabolic response in muscle that can account for the protein wasting associated with uremia.
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PMID:Acidosis and glucocorticoids interact to provoke muscle protein and amino acid catabolism. 761 86

It is well established that chronic renal failure is associated with loss of lean body mass. Possible explanations for protein losses include a limited ability to reduce essential amino acid oxidation and protein degradation when dietary protein is low. 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 stimulates the degradation of muscle protein. We find that the ATP-ubiquitin-proteasome-dependent pathway causing muscle protein degradation is activated by acidosis. Glucocorticoids are required but are not sufficient to elicit this catabolic response.
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PMID:Metabolic acidosis stimulates protein metabolism in uremia. 867 27

Muscle protein degradation is accelerated by the acidosis associated with chronic renal failure. In isolated muscles from acidotic rats, a cytosolic, ATP-dependent proteolytic pathway is stimulated with a concurrent increase in the abundance of mRNAs encoding ubiquitin and subunits of the 26S proteasome complex associated with this degradative pathway. Adrenalectomy (ADX) prevents the acidosis-induced increase in muscle protein degradation unless high physiologic doses of glucocorticoids are administered to acidotic, adrenalectomized rats. We have examined the roles that acidosis and glucocorticoids have in the increase in mRNAs encoding proteins of the ATP-dependent-ubiquitin-proteasome proteolytic pathway in ADX rats. We found that ubiquitin and proteasome C2 and C9 subunit mRNA levels are increased in the white fiber, extensor digitorus longus (EDL) and mixed fiber, gastrocnemius muscles from acidotic ADX rats that received dexamethasone whereas acidosis alone or dexamethasone alone failed to increase these mRNAs. In contrast, acidosis plus dexamethasone decreased the total RNA content in both muscles. These data suggest that in muscle, the response to acidosis involves the specific activation of the ATP-ubiquitin-proteasome proteolytic pathway. Moreover, glucocorticoids are required but not directly responsible for the acidosis-induced increase in the mRNAs encoding proteins of this degradative pathway.
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PMID:Necessary but not sufficient: the role of glucocorticoids in the acidosis-induced increase in levels of mRNAs encoding proteins of the ATP-dependent proteolytic pathway in rat muscle. 867 30

Patients with chronic renal failure suffer from a muscle wasting syndrome that is characterized by loss of lean body mass and negative nitrogen balance. Evidence is provided indicating that metabolic acidosis plays a major role in initiating these adverse effects. In particular, we discuss findings suggesting that metabolic acidosis mitigates its effects by activating the cytosolic ubiquitin proteasome proteolytic pathway. Additional evidence that metabolic acidosis alters vitamin D and parathyroid hormone levels is provided. Therapy that includes correction of the metabolic acidosis with alkali in the form of sodium bicarbonate supplements has significant therapeutic implications for uremic patients with even mild degrees of metabolic acidosis.
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PMID:Metabolic acidosis as a uremic toxin. 873 59

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.
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PMID:Cellular mechanisms of catabolism activated by metabolic acidosis. 882 Dec 2

In chronic renal failure (CRF), the ATP-dependent, ubiquitin-proteasome proteolytic pathway is activated with concurrent increases in the transcription of genes encoding proteins of this pathway in muscle. We have shown that the stimuli for these responses include acidosis and glucocorticoids, but other endocrine abnormalities in CRF (e.g., insulin resistance) could contribute to these responses. In fact, a major effect of insulin in muscle is to suppress protein degradation. To examine whether insulin influences the ubiquitin-proteasome pathway, we measured protein degradation in incubated epitrochlearis muscles of diabetic and pair-fed control rats. Muscle proteolysis was increased in pathways that do not involve lysosomes or Ca(2+)-dependent proteases; but MG132, a protease inhibitor that blocks ATP synthesis, eliminated the accelerated rate of protein degradation in diabetic rat muscles. Diabetes mellitus also increased levels of mRNAs encoding ubiquitin (334%), E2 ubiquitin-conjugating enzyme (247%), and the C3 (320%), C5 (349%), and C9 (216%) proteasome subunits in muscle. Finally, transcription of the ubiquitin gene in diabetic rat muscles was increased. Diabetic rats were acidotic, but eliminating acidemia by giving NaHCO3 did not block the increase in muscle proteolysis. Giving diabetic rats insulin prevented the excessive muscle proteolysis, suggesting that insulin acts as a suppressor of the ubiquitin-proteasome pathway. Thus, the insulin resistance of uremia could contribute to muscle protein wasting in CRF.
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PMID:Signals regulating accelerated muscle protein catabolism in uremia. 938 16

Loss of lean body mass is common in patients with acute or chronic renal failure but the mechanisms causing this loss are only beginning to be understood. One mechanism involves an inability of uremic patients to activate the critical metabolic responses that maintain protein balance when dietary protein is limited. Metabolic responses to dietary protein restriction include a sharp reduction in the degradation of essential amino acids and protein; changes in protein synthesis are less reliable. If uremia prevents suppression of essential amino acid or protein degradation when dietary protein is reduced by anorexia, negative nitrogen balance and loss of lean body mass will ensue. One complication of uremia, metabolic acidosis, stimulates the degradation of branched-chain amino acids and proteins and therefore blocks the ability of the patient to respond to a low-protein diet. The mechanisms require glucocorticoids and involve increased activity of branched-chain keto acid dehydrogenase and the ubiquitin-proteasome proteolytic pathway; there also is increased transcription of genes encoding components of enzymes involved in the pathways. Besides acidosis, a low insulin concentration and cytokines activate the ubiquitin-proteasome proteolytic pathway. Understanding how proteolysis is activated, including how these genes are stimulated, is important because the same pathways are activated in diabetes, cancer, sepsis, burns, starvation, and muscle denervation. Activation of the ubiquitin-proteasome pathway leads to reduced lean body mass.
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PMID:Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. 949 77

Decreased muscle mass in patients with chronic renal failure (CRF) can be caused by mechanisms that activate the ubiquitin-proteasome proteolytic system. This system accelerates the degradation of muscle protein. Concurrent with muscle protein breakdown, there is an increase in transcription of genes encoding components of this pathway, including ubiquitin and subunits of the proteasome. Potential activating signals include metabolic acidosis which stimulates proteolysis in CRF patients and in muscle of rats with CRF by a mechanism involving glucocorticoids. In CRF patients, there is insulin resistance and high circulating levels of tumor necrosis factor and other cytokines. As the ubiquitin-proteasome proteolytic system is activated in acute diabetes and in catabolic conditions associated with high levels of circulating cytokines, these factors could also activate this pathway. Consequently, we examined whether the transcription factor activated by certain cytokines, NF-kappaB, is involved in the transcriptional regulation of subunits of the 26S proteasome complex. The results suggest that cytokines may be involved in the regulation of muscle protein degradation in uremia.
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PMID:Mechanisms causing muscle proteolysis in uremia: the influence of insulin and cytokines. 1068 42

Much has been learned from animal studies in chronic renal failure that is germane to clinical studies because animal models parallel human responses. Such studies have affirmed that correction of metabolic acidosis has a favorable effect on protein metabolism, nitrogen balance and growth. In the presence of metabolic acidosis, catabolism is increased in uremia. Glucocorticoids are involved in accelerating protein degradation in muscle, which results in loss of lean body mass, while a low insulin level appears to play a permissive role in accelerating increased catabolism. Cellular mechanisms mediating these changes include upregulation of the ubiquitin-proteasome pathway and branched-chain ketoacid dehydrogenase enzyme activity in muscle. Many of these findings from rat studies have been confirmed in human studies and have important clinical implications because correction of metabolic acidosis improves nutritional status and blunts the associated increase in protein catabolism.
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PMID:Twice-told tales of metabolic acidosis, glucocorticoids, and protein wasting: what do results from rats tell us about patients with kidney disease? 1092 49

Loss of muscle mass is a risk factor for mortality in chronic renal failure (CRF). Catabolic signals (eg, acidosis, glucocorticoids, insulin resistance) present in CRF stimulate the ubiquitin-proteasome proteolytic pathway in muscle but the activation mechanism(s) have been elusive. We have identified distinct mechanisms that may work in concert to increase the degradation of muscle proteins. Glucocorticoids increase the transcription of genes encoding components of the ubiquitin-proteasome pathway, thereby increasing the proteolytic capacity of muscle cells. Another signal could be a decreased response to insulin because acute diabetes is a potent stimulus for protein degradation by the ubiquitin-proteasome pathway and CRF impairs insulin signaling in muscle. Together, these responses increase the breakdown of muscle, contributing to protein malnutrition in CRF.
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PMID:Molecular mechanisms regulating protein turnover in muscle. 1115 74


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