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)

A characteristic response to injury is a dramatic loss of skeletal muscle protein owing to increased muscle protein breakdown. Over the past decade, numerous studies have indicated that up-regulation of the ubiquitin-proteasome system is a common mechanism underlying such injury-induced muscle proteolysis. However, a recent study using a single-impact trauma to the gastrocnemius muscle found that, although the rate of muscle proteolysis was dramatically increased, the ubiquitin-proteasome system was not involved. Rather, an increase in lysosomal activity, through infiltration of the damaged tissue by mononuclear macrophages, is responsible for the high rates of protein breakdown.
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PMID:Not all injury-induced muscle proteolysis is due to increased activity of the ubiquitin/proteasome system: evidence for up-regulation of macrophage-associated lysosomal proteolysis in a model of local trauma. 1263 62

Muscle atrophy is a common consequence of catabolic conditions like kidney failure, cancer, sepsis, and acute diabetes. Loss of muscle protein is due primarily to activation of the ubiquitin-proteasome proteolytic system. The proteolytic responses to catabolic signals include increased levels of mRNA that encode various components of the system. In the case of two genes, the proteasome C3 subunit and ubiquitin UbC, the higher levels of mRNA result from increased transcription but the mechanisms of transactivation differ between them. This review summaries the evidence that cachectic signals activate a program of selective transcriptional responses in muscle that frequently occurs coordinately with increased protein destruction.
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PMID:Increased transcription of ubiquitin-proteasome system components: molecular responses associated with muscle atrophy. 1267 54

There is little information on the mechanisms responsible for muscle recovery following a catabolic condition. To address this point, we reloaded unweighted animals and investigated protein turnover during recovery from this highly catabolic state and the role of proteolysis in the reorganization of the soleus muscle. During early recovery (18 h of reloading) both muscle protein synthesis and breakdown were elevated (+65%, P<0.001 and +22%, P<0.05, respectively). However, only the activation of non-lysosomal and Ca(2+)-independent proteolysis was responsible for increased protein breakdown. Accordingly, mRNA levels for ubiquitin and 20S proteasome subunits C8 and C9 were markedly elevated (from +89 to +325%, P<0.03) and actively transcribed as shown by the analysis of polyribosomal profiles. In contrast, both cathepsin D and 14-kDa-ubiquitin conjugating enzyme E2 mRNA levels decreased, suggesting that the expression of such genes is an early marker of reversed muscle wasting. Following 7 days of reloading, protein synthesis was still elevated and there was no detectable change in protein breakdown rates. Accordingly, mRNA levels for all the proteolytic components tested were back to control values even though an accumulation of high molecular weight ubiquitin conjugates was still detectable. This suggests that soleus muscle remodeling was still going on. Taken together, our observations suggest that enhanced protein synthesis and breakdown are both necessary to recover from muscle atrophy and result in catch-up growth. The observed non-coordinate regulation of proteolytic systems is presumably required to target specific classes of substrates (atrophy-specific protein isoforms, damaged proteins) for replacement and/or elimination.
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PMID:Regulation of proteolysis during reloading of the unweighted soleus muscle. 1267 58

Insulin-dependent diabetes mellitus is known to go along with enhanced muscle protein breakdown. Since evidence has been presented that the ubiquitin-proteasome system is significantly involved in muscle wasting under this condition, we have investigated, whether this biological role goes along with alterations of the proteasome system in skeletal muscle of streptozotocin-diabetic rats. Previously, we have found a drop of overall proteasome activity in muscle extracts of rats after induction of diabetes but no change in total amount of 20S proteasome was detected. In the present investigation under the same diabetic conditions we have measured a significant decrease in the amount of proteasome activator PA28, a finding that explains the loss of total proteasome activity. Since increased mRNA levels of proteasome subunits have been measured in muscle tissue of rats after induction of diabetes, we have isolated and purified 20S proteasomes from muscle tissue of control and 6 days diabetic rats. The specific chymotrypsin-like, trypsin-like, and peptidylglutamylpeptide-hydrolysing activities of proteasomes from diabetic and control rats were found to be not significantly different. Therefore, we have fractionated 20S proteasomes into their subtypes and detected that induction of diabetes mellitus effects a redistribution of subtypes of all three proteasome populations but only the increase in subtype V (immuno-subtype) was statistically significant. This altered subtype pattern obviously meets the requirements to the system under wasting conditions. Since this process goes along with de novo biogenesis of 20S proteasomes, it most likely explains the phenomenon of elevated mRNA concentrations of proteasome subunits after induction of diabetes mellitus.
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PMID:Alteration of 20S proteasome-subtypes and proteasome activator PA28 in skeletal muscle of rat after induction of diabetes mellitus. 1267 65

The goal of this research was to evaluate the roles of calpains and their interactions with the proteasome and the lysosome in degradation of individual sarcomeric and cytoskeletal proteins in cultured muscle cells. Rat L8-CID muscle cells, in which we expressed a transgene calpain inhibitor (CID), were used in the study. L8-CID cells were grown as myotubes after which the relative roles of calpain, proteasome and lysosome in total protein degradation were assessed during a period of serum withdrawal. Following this, the roles of proteases in degrading cytoskeletal proteins (desmin, dystrophin and filamin) and of sarcomeric proteins (alpha-actinin and tropomyosin) were assessed. Total protein degradation was assessed by release of radioactive tyrosine from pre-labeled myotubes in the presence and absence of protease inhibitors. Effects of protease inhibitors on concentrations of individual sarcomeric and cytoskeletal proteins were assessed by Western blotting. Inhibition of calpains, proteasome and lysosome caused 20, 62 and 40% reductions in total protein degradation (P<0.05), respectively. Therefore, these three systems account for the bulk of degradation in cultured muscle cells. Two cytoskeletal proteins were highly-sensitive to inhibition of their degradation. Specifically, desmin and dystrophin concentrations increased markedly when calpain, proteasome and lysosome activities were inhibited. Conversely, sarcomeric proteins (alpha-actinin and tropomyosin) and filamin were relatively insensitive to the addition of protease inhibitors to culture media. These data demonstrate that proteolytic systems work in tandem to degrade cytoskeletal and sarcomeric protein complexes and that the cytoskeleton is more sensitive to inhibition of degradation than the sarcomere. Mechanisms, which bring about changes in the activities of the proteases, which mediate muscle protein degradation are not known and represent the next frontier of understanding needed in muscle wasting diseases and in muscle growth biology.
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PMID:Degradation of sarcomeric and cytoskeletal proteins in cultured skeletal muscle cells. 1460 48

These experiments were done to clarify that the differential effects of thyroxine (T(4)) and triiodothyronine (T(3)) on skeletal muscle protein turnover are caused by their roles on ATP production. Primary cultured chick muscle cells were treated with a physiological level of T(4) (60 ng/ml), T(3) (12 ng/ml), or ATP (0.5 mM) for 6 days and the protein content, ATP production, proteasome activity, and myofibrillar protein breakdown were measured. The protein content measured as an index of cell growth was not affected by T(4), T(3), or ATP. The cellular ATP level was increased by T(3) and ATP, but not by T(4). Proteasome activity and N(tau)-methylhistidine (MeHis) release measured as an index of myofiblillar protein breakdown was also increased by T(3) and ATP, but not by T(4). These results indicate that T(3) but not T(4) increases ATP production followed by an increase in proteasome activity, and thus stimulates myofibrillar proteolysis.
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PMID:Triiodothyronine but not thyroxine accelerates myofibrillar proteolysis via ATP production in cultured muscle cells. 1464 7

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.
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PMID:Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. 1470 15

In previous studies, insulin-like growth factor-I (IGF-I) inhibited glucocorticoid-induced muscle protein breakdown, but the intracellular mechanisms of this effect of IGF-I are not well understood. The purpose of the present study was to test the hypothesis that IGF-I inhibits multiple proteolytic pathways in dexamethasone-treated cultured L6 myotubes. Myotubes were treated with 1 microM dexamethasone for 6 hours in the absence or presence of 0.1 microg/ml of IGF-I. Protein degradation was determined by measuring the release of trichloroacetic acid-soluble radioactivity from proteins prelabeled with 3H-tyrosine. The contribution of lysosomal, proteasomal-dependent, and calpain-dependent proteolysis to the inhibitory effect of IGF-I on protein degradation was assessed by using inhibitors of the individual proteolytic pathways (methylamine, beta-lactone, and E64, respectively). In addition, the influence of IGF-I on cathepsin B, proteasome, and calpain activities was determined. Treatment of L6 myotubes with dexamethasone resulted in an approximately 20% increase in protein degradation. This effect of dexamethasone was completely blocked by IGF-I. When the different protease inhibitors were used, results showed that IGF-I inhibited lysosomal, proteasomal-dependent, and calpain-dependent proteolysis by 70, 44, and 41%, respectively. Additionally, IGF-I blocked the dexamethasone-induced increase in cathepsin B, proteasome, and calpain activities. The present results suggest that IGF-I inhibits glucocorticoid-induced muscle proteolysis by blocking multiple proteolytic pathways.
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PMID:Insulin-like growth factor-I blocks dexamethasone-induced protein degradation in cultured myotubes by inhibiting multiple proteolytic pathways: 2002 ABA paper. 1472 48

Protein undernutrition inhibits adenosine triphosphate (ATP)-dependent muscle protein degradation-a hallmark of the proteasome system. Here we report decreased myofibrillar protein degradation during dietary protein restriction without a concomitant decrease in proteasome gene expression, proteasome protein abundance, or proteasome in vivo fractional synthesis rate. Healthy human subjects consuming the average minimum adult protein requirement (0.71 g x kg(-1) fat-free mass x d(-1)) exhibited substantially lower (68%) excretion of 3-methylhistidine, an indicator of myofibrillar protein breakdown, when compared with subjects consuming an ample, American-style protein intake (1.67 g x kg(-1) fat-free mass x d(-1)). However, they displayed no difference in the expression of mRNA for proteasome subunits C2 or C3, in the content of C2 protein, or in the rate of incorporation of stable isotopically labeled l-[1-(13)C]-leucine into proteasome proteins. The results demonstrate that nutritional inhibition of myofibrillar protein degradation does not involve suppression in vivo of proteasome production in man. This suggests that other elements of the ubiquitin-proteasome system, such as ubiquitination pathways, are more important than proteasome abundance in the nutritional regulation of skeletal muscle mass.
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PMID:Proteasome production in human muscle during nutritional inhibition of myofibrillar protein degradation. 1501 47

Skeletal muscle wasting is a prominent feature of cancer cachexia and involves decreased muscle protein synthesis and increased activity of the ubiquitin-proteasome pathway of protein degradation. We report that both indomethacin and ibuprofen improved body weight and weight of the gastrocnemius muscle in tumor-bearing mice. Ibuprofen increased the soluble protein content of the muscle without affecting muscle levels of phosphorylated p70 S6 kinase, a ribosomal kinase involved in protein synthesis. Paradoxically, indomethacin increased levels of ubiquitin-conjugated proteins. Further study is needed to understand the mechanism of action by which indomethacin and ibuprofen preserve body weight and muscle mass in the tumor-bearing mice. The data suggest that ibuprofen may have beneficial effects in the treatment of cancer cachexia.
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PMID:Indomethacin and ibuprofen preserve gastrocnemius muscle mass in mice bearing the colon-26 adenocarcinoma. 1514 70


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