Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several observations have suggested that the enhanced proteolysis and atrophy of skeletal muscle in various pathological states is due primarily to activation of the ubiquitin-proteasome pathway. To test this idea, we investigated whether peptide aldehyde inhibitors of the proteasome, N-acetyl-leucyl-leucyl-norleucinal (LLN), or the more potent CBZ-leucyl-leucyl-leucinal (MG132) suppressed proteolysis in incubated rat skeletal muscles. These agents (e.g., MG132 at 10 microM) inhibited nonlysosomal protein breakdown by up to 50% (P < 0.01), and this effect was rapidly reversed upon removal of the inhibitor. The peptide aldehydes did not alter protein synthesis or amino acid pools, but improved overall protein balance in the muscle. Upon treatment with MG132, ubiquitin-conjugated proteins accumulated in the muscle. The inhibition of muscle proteolysis correlated with efficacy against the proteasome, although these agents could also inhibit calpain-dependent proteolysis induced with Ca2+. These inhibitors had much larger effects on proteolysis in atrophying muscles than in controls. In the denervated soleus undergoing atrophy, the increase in ATP-dependent proteolysis was reduced 70% by MG132 (P < 0.001). Similarly, the rise in muscle proteolysis induced by administering thyroid hormones was reduced 40-70% by the inhibitors. Finally, in rats made septic by cecal puncture, the increase in muscle proteolysis was completely blocked by MG132. Thus, the enhanced proteolysis in many catabolic states (including denervation, hyperthyroidism, and sepsis) is due to a proteasome-dependent pathway, and inhibition of proteasome function may be a useful approach to reduce muscle wasting.
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PMID:Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles. 920 72

Glucocorticoids signal enhanced proteolysis in various instances of muscle atrophy and increased gene expression of components of the lysosomal, Ca(2+)-dependent, and/or ubiquitin-proteasome proteolytic pathways in both rat skeletal muscle and myotubes. Cushing's syndrome is characterized by chronic excessive glucocorticoid production, which results in muscle wasting. We report here no change in messenger RNA levels for cathepsin D (a lysosomal proteinase), m-calpain (a Ca(2+)-activated proteinase), ubiquitin, 14-kDa ubiquitin-activating enzyme E2, and 20S proteasome subunits (i.e. critical components of the ubiquitin-proteasome proteolytic process) in skeletal muscle from such patients. Thus, in striking contrast with animal studies, glucocorticoids did not regulate the expression of muscle proteolytic genes in Cushing's syndrome. In humans, messenger RNA levels, for at least ubiquitin and proteasome subunits, are elevated in acute situations of muscle wasting, such as head trauma or sepsis. Because Cushing's syndrome is a chronic catabolic condition, we suggest that the lack of regulation of proteolytic genes in such patients may represent an adaptive regulatory mechanisms, preventing sustained increased protein breakdown and avoiding rapid muscle wasting.
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PMID:Glucocorticoids do not regulate the expression of proteolytic genes in skeletal muscle from Cushing's syndrome patients. 928 62

There is no doubt that acute renal failure (ARF) is associated with enhanced protein breakdown. It has been shown that protein split products can be measured in plasma samples of these patients. On the other hand, ARF frequently occurs in conditions of increased metabolic stress which leads to enhanced protein catabolism. Muscle wasting, loss of lean body weight, and a negative nitrogen balance result in malnutrition which considerably increases morbidity and mortality. Besides the accumulation of uremic toxins, several other factors are involved in the accelerated proteolysis in ARF. Metabolic acidosis appears to be one of the major catabolic factors in chronic renal failure, and probably in ARF as well. Insulin resistance, which is commonly attributed to uremia, also increases protein degradation. However, this derangement of carbohydrate metabolism is not directly accessible to therapy, in contrast to acidosis, which can be easily corrected by bicarbonate administration. There is further evidence that glucocorticoid excess contributes to the enhanced muscle proteolysis in ARF. Moreover, several studies have demonstrated that only in the presence of both glucocorticoids and acidosis could proteolysis occur. Investigation of the cellular mechanism by which muscle proteins are degraded indicates the importance of the cytosolic, soluble ATP- and ubiquitin-dependent proteolytic system. Successful treatment of various catabolic conditions with recombinant human growth hormone and insulin-like growth factor-I seems to be a promising strategy in severely catabolic patients with ARF. Anticytokine therapy appears to be another promising treatment in the course of catabolic illness due to sepsis; however, clinical application is still in its infancy.
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PMID:Protein catabolism in acute renal failure. 938 14

The daily turnover of protein amounts to 280 g in an adult weighing 70 kg but the metabolic processes responsible for protein turnover are only just beginning to be understood. In cells, the major pathway of protein degradation is the ubiquitin-proteasome pathway and protein flux through this pathway is precisely regulated. In catabolic conditions such as uremia, activity of the ubiquitin-proteasome pathway increases, resulting in degradation of muscle protein. In addition to increased protein degradation, gene transcription is activated, resulting in higher levels of the mRNAs encoding ubiquitin and proteasome subunits. The signals activating this pathway include metabolic acidosis and glucocorticoids but must be more diverse since the pathway is also activated in response to starvation, sepsis, cancer, muscle denervation, thermal injury, and acute diabetes. Understanding how the pathway is controlled could lead to the prevention of muscle loss in uremia and other conditions.
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PMID:Cellular mechanisms controlling protein degradation in catabolic states. 938 15

Muscle catabolism is a characteristic metabolic response to sepsis, severe infection, and injury. In patients with severe and protracted sepsis, the catabolic response results in muscle wasting and fatigue, which may adversely affect the outcome in these patients. An understanding of the regulation of muscle protein breakdown during sepsis and the mechanisms involved is important from a clinical standpoint and is essential for the development of new therapeutic modalities to prevent protein loss from muscle tissue. Studies in septic patients and experimental animals have provided evidence that the myofibrillar proteins actin and myosin are particularly sensitive to the effects of sepsis. Among the factors that regulate muscle protein breakdown during sepsis, the proinflammatory cytokines tumor necrosis factor and interleukin-1, together with glucocorticoids, are the principal mediators. Intracellular protein breakdown is regulated by multiple proteolytic pathways. Among these, the energy-ubiquitin-dependent pathway accounts for a major portion of muscle protein breakdown during sepsis. The development of specific proteasome inhibitors may make it possible in the future to target the molecular mechanisms of sepsis-induced increase in muscle proteolysis. Such treatment may prove an important avenue to reduce the metabolic cost in patients with severe infection or sepsis.
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PMID:Sepsis: stimulation of energy-dependent protein breakdown resulting in protein loss in skeletal muscle. 945 37

Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle. The 20S proteasome is the catalytic core of the ubiquitin-dependent proteolytic pathway. We tested the effects in vitro of the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinal-L-norleucinal (LLnL) and lactacystin on protein breakdown in incubated muscles from septic rats. LLnL resulted in a dose- and time-dependent inhibition of protein breakdown in muscles from septic rats. Lactacystin blocked both total and myofibrillar muscle protein breakdown. In addition to inhibiting protein breakdown, LLnL reduced muscle protein synthesis and increased ubiquitin mRNA levels, probably reflecting inhibited proteasome-associated ribonuclease activity. Inhibited muscle protein breakdown caused by LLnL or lactacystin supports the concept that the ubiquitin-proteasome pathway plays a central role in sepsis-induced muscle proteolysis. The results suggest that muscle catabolism during sepsis may be inhibited by targeting specific molecular mechanisms of muscle proteolysis.
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PMID:Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors. 945 95

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

The rapid loss of muscle mass that accompanies many disease states, such as cancer or sepsis, is primarily a result of increased protein breakdown in muscle, and several observations have suggested an activation of the ubiquitin-proteasome system. Accordingly, in extracts of atrophying muscles from tumor-bearing or septic rats, rates of 125I-ubiquitin conjugation to endogenous proteins were found to be higher than in control extracts. On the other hand, in extracts of muscles from hypothyroid rats, where overall proteolysis is reduced below normal, the conjugation of 125I-ubiquitin to soluble proteins decreased by 50%, and treatment with triiodothyronine (T3) restored ubiquitination to control levels. Surprisingly, the N-end rule pathway, which selectively degrades proteins with basic or large hydrophobic N-terminal residues, was found to be responsible for most of these changes in ubiquitin conjugation. Competitive inhibitors of this pathway that specifically block the ubiquitin ligase, E3alpha, suppressed most of the increased ubiquitin conjugation in the muscle extracts from tumor-bearing and septic rats. These inhibitors also suppressed ubiquitination in normal extracts toward levels in hypothyroid extracts, which showed little E3alpha-dependent ubiquitination. Thus, the inhibitors eliminated most of the differences in ubiquitination under these different pathological conditions. Moreover, 125I-lysozyme, a model N-end rule substrate, was ubiquitinated more rapidly in extracts from tumor-bearing and septic rats, and more slowly in those from hypothyroid rats, than in controls. Thus, the rate of ubiquitin conjugation increases in atrophying muscles, and these hormone- and cytokine-dependent responses are in large part due to activation of the N-end rule pathway.
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PMID:Rates of ubiquitin conjugation increase when muscles atrophy, largely through activation of the N-end rule pathway. 977 May 32

We tested the role of interleukin-6 (IL-6) in sepsis-induced muscle proteolysis by determining ubiquitin mRNA levels and protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated IL-6 knockout and wild-type mice. In addition, the effect of treatment of mice with human recombinant IL-6 on muscle protein breakdown rates was determined. Finally, protein breakdown rates were measured in myotubes treated for up to 48 h with different concentrations of IL-6. Sepsis in wild-type mice resulted in an approximately ninefold increase in plasma IL-6 levels, whereas IL-6 was not detectable in plasma of sham-operated or septic IL-6 knockout mice. Total and myofibrillar muscle protein breakdown rates were increased by approximately 30% and threefold, respectively, in septic IL-6 wild-type mice with an almost identical response noted in septic IL-6 knockout mice. Ubiquitin mRNA levels determined by dot blot analysis were increased during sepsis in muscles from both IL-6 knockout and wild-type mice, although the increase was less pronounced in IL-6 knockout than in wild-type mice. Treatment of normal mice or of cultured L6 myotubes with IL-6 did not influence protein breakdown rates. The present results suggest that IL-6 does not regulate muscle proteolysis during sepsis.
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PMID:Sepsis in mice stimulates muscle proteolysis in the absence of IL-6. 984 88

Previous studies provided evidence that sepsis is associated with increased ubiquitin-proteasome-dependent protein breakdown in skeletal muscle. The 14-kDa ubiquitin-conjugating enzyme (E214k) has been proposed to be a key regulator of the ubiquitin proteolytic pathway. We tested the hypothesis that E214k message and protein levels are increased in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham operated. E214k mRNA and protein levels were quantitated after Northern and Western blot analysis, respectively, 16 h after CLP or sham operation. Sepsis resulted in a 70% increase in the 1. 2-kb E214k transcript in the fast-twitch extensor digitorum longus muscle, whereas no changes were seen in the slow-twitch soleus muscle. E214k protein levels were not influenced by sepsis in any of the muscles studied. Although the changes in the expression of the E214k 1.2-kb transcript paralleled the differential effect of sepsis on protein breakdown in fast- and slow-twitch muscle, the potential role of E214k in the regulation of sepsis-induced muscle proteolysis needs to be interpreted with caution, because the results demonstrated that increased message levels were not associated with increased E214k protein levels.
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PMID:Sepsis is associated with increased ubiquitinconjugating enzyme E214k mRNA in skeletal muscle. 995 Sep 26


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