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 phenotypic feature of aging is skeletal muscle wasting. It is characterized by a loss of muscle mass and strength. Age-related loss of muscle mass occurs through a reduction in the rate of protein synthesis, an increase in protein degradation or a combination of both. However, the underlying mechanism is still poorly understood. To test the hypothesis that the ubiquitin-proteasome pathway contributes to this phenomenon, we studied MuRF1 and atrogin-1 expression in Tibialis Anterior muscle of aged rats. These two E3 ligases are considered as sensitive markers of muscle protein degradation by the ubiquitin-proteasome system. Our results revealed that, in skeletal muscle of aged rats, the decline in muscle mass is accompanied by an increase in the level of oxidized proteins and ubiquitin conjugates (90%) whereas the functionality of the proteasome remains constant compared to young rats. Furthermore, the level of both MuRF1 and atrogin-1 mRNA is markedly up-regulated in aged muscle (respectively x2 and x2.5). Taken together these data argue for the involvement of the ubiquitin-proteasome pathway in sarcopenia of fast-twitch muscle, in particular through increased expression of MuRF1 and atrogin-1. Moreover, we observed a decrease in the IGF-1/Akt signalling pathways and elevated level of TNFalpha mRNA in aged rat muscle. Therefore, IGF-1/Akt and TNFalpha represent potential mediators implicated in the regulation of MuRF1 and atrogin-1 genes during aging.
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PMID:Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle. 1694 34

The regulation of cell size depends on a delicate balance between protein synthesis and breakdown. Skeletal and cardiac muscle adapt to hormonal and neuronal stimuli and can rapidly hypertrophy and atrophy; however, the extent to which these processes occur in smooth muscle is less clear. Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1). Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs. While these two genes are similarly induced in all types of muscle during rapid loss of cell mass, other striated muscle atrophy-specific transcriptional changes are not observed during uterine involution, suggesting different underlying molecular mechanisms. These results raise the possibility that activation of atrogin-1 and MuRF-1 may be a common general adaptation in cells undergoing a rapid reduction in size.
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PMID:Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period. 1700 54

Patients with chronic kidney disease (CKD), including those who are treated with hemodialysis, frequently develop hypoalbuminemia and a decrease in body weight. These abnormalities are usually attributed to malnutrition, but true malnutrition (ie, a disorder due to an abnormal diet) is rarely the mechanism causing decreased protein stores. Hypoalbuminemia is closely related to evidence of inflammation, and a decrease in muscle mass is caused by activation of muscle protein breakdown. In uremic rodents and patients, the initial step in the loss of muscle protein is activation of caspase-3, which cleaves the complex structure of muscle to provide substrates for the ubiquitin-proteasome pathway (UPP). The activity of caspase-3 can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of a muscle biopsy specimen. Abnormalities in cell signaling activate caspase-3 and the UPP; a key abnormality is decreased activity in the phosphatidylinositol-3-kinase/Akt pathway, leading to activation of caspase-3 and a specific E3 ubiquitin conjugating enzyme, atrogin-1/MAFbx. Inflammatory cytokines also represent a potential cell signaling abnormality that activates muscle protein breakdown, possibly because cytokines activate the E3 ubiquigin conjugating enzyme, MuRF1. An understanding of these pathways could help the clinician to identify therapeutic targets for preventing loss of muscle protein.
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PMID:Malnutrition is an unusual cause of decreased muscle mass in chronic kidney disease. 1719 36

TWEAK cytokine has been implicated in several biological responses including inflammation, angiogenesis, and osteoclastogenesis. We have investigated the role of TWEAK in regulating skeletal muscle mass. Addition of soluble TWEAK protein to cultured myotubes reduced the mean myotube diameter and enhanced the degradation of specific muscle proteins such as CK and MyHCf. The effect of TWEAK on degradation of MyHCf was stronger than its structural homologue, TNF-alpha. TWEAK increased the ubiquitination of MyHCf and the transcript levels of atrogin-1 and MuRF1 ubiquitin ligases. TWEAK inhibited phosphorylation of Akt kinase and its downstream targets GSK-3beta, FOXO1, mTOR, and p70S6K. Furthermore, TWEAK increased the activation of NF-kappaB transcription factor in myotubes. Adenoviral-mediated overexpression of IkappaB alpha deltaN (a degradation-resistant mutant of NF-kappaB inhibitory protein IkappaB alpha) in myotubes blocked the TWEAK-induced degradation of MyHCf. Chronic administration of TWEAK in mice resulted in reduced body and skeletal muscle weight with an associated increase in the activity of ubiquitin-proteasome system and NF-kappaB. Finally, muscle-specific transgenic overexpression of TWEAK decreased the body and skeletal muscle weight in mice. Collectively, our data suggest that TWEAK induces skeletal muscle atrophy through inhibition of the PI3K/Akt signaling pathway and activation of the ubiquitin-proteasome and NF-kappaB systems.
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PMID:TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. 1731 37

New evidence has demonstrated that the expression of major genes, termed atrogenes, controls the ubiquitin-proteasome proteolytic pathway. The present work aimed to study the impact of insulin and amino acids on the expression of one of these atrogenes, the E3 ubiquitin ligase Muscle Atrophy F box (MAFbx, also called atrogin-1), in quail muscle (QT6) fibroblasts. First, we characterized atrogin-1 in QT6 cells and demonstrated the insulin sensitivity of these cells. Second, we showed that insulin reduced atrogin-1 mRNA via the phosphatidylinositol-3'kinase (PI3K)/protein kinase B (PKB or AKT)/target of rapamycin (TOR) pathway. Atrogin-1 expression also depended on the availability of an individual amino acid, i.e., methionine. Moreover, the amino acid-induced reduction of atrogin-1 was inhibited by rapamycin, indicating the involvement of the TOR pathway in such regulation. In conclusion, expression of the ubiquitin ligase atrogin-1 is regulated by both insulin and amino acids through the TOR pathway.
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PMID:Insulin and amino acid availability regulate atrogin-1 in avian QT6 cells. 1741 4

PPARalpha agonism impairs mitochondrial function, but the effect of PPARdelta agonism on mitochondrial function is equivocal. Furthermore, PPARalpha and delta agonism increases muscle fatty acid oxidation, potentially via activation of FOXO1 signalling and PDK4 transcription. Since FOXO1 activation has also been suggested to increase transcription of MAFbx and MuRF-1, and thereby the activation of ubiquitin-proteasome mediated muscle proteolysis, this raises the possibility that muscle fuel selection and the induction of a muscle atrophy programme could be regulated by a single common signalling pathway. We therefore investigated the effect of PPARdelta (delta) agonist, GW610742, administration on muscle mitochondrial function, fuel regulation, and atrophy and growth related signalling pathways in vivo. Twenty-four male Wistar rats received vehicle or GW610742 (5 and 100 mg per kg body mass (bm)) orally for 6 days. Soleus muscle was used to determine maximal rates of ATP production (MRATP) in isolated mitochondria, gene and protein expression, and enzyme activities. MRATP were unchanged by GW610742. Muscle PDK2 and PDK4 mRNA expression increased with GW610742 (100 mg (kg bm)(-1)) compared to vehicle (P<0.05), and was paralleled by a twofold increase in PDK4 protein expression (P<0.05). The activity of beta-hydroxyacyl-CoA dehydrogenase increased with GW610742 (P<0.05). Muscle MuRF1 and MAFbx mRNA expression was increased by GW610742 (100 mg (kg bm)(-1)) compared to vehicle (P<0.05), and was matched by increased protein expression (P<0.001), whilst Akt1 protein declined (P<0.05). There was no effect of GW610742 on 20S proteasome activity and mRNA expression, or the muscle DNA: protein ratio. GW610742 switched muscle fuel metabolism towards decreased carbohydrate use and enhanced lipid utilization, but did not induce mitochondrial dysfunction. Furthermore, GW610742 initiated a muscle atrophy programme, possibly via changes in the Akt1/FOXO/MAFbx and MuRF1 signalling pathway.
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PMID:PPARdelta agonism induces a change in fuel metabolism and activation of an atrophy programme, but does not impair mitochondrial function in rat skeletal muscle. 1754 Jul

In skeletal muscle, AMP-activated protein kinase (AMPK) is a metabolic master switch regulating glucose and lipid metabolism. Recently, AMPK has been implicated in the control of protein synthesis in skeletal muscle, but the effect of AMPK activation on myofibrillar protein degradation has yet to be elucidated. The present study was designed to examine the effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR)-induced AMPK signaling on effector mechanisms of myofibrillar protein degradation and the expression of atrophy-related genes (atrogin-1/MAFbx, MuRF1, proteasome C2 subunit, calpains, cathepsin B, and caspase-3) in C2C12 myotubes. AICAR stimulated myofibrillar protein degradation (as measured by N(tau)-methylhistidine release), while also increasing the levels of atrogin-1/MAFbx and MuRF1 mRNA, but the expression of other atrophy-related genes was not enhanced by AICAR treatment in C2C12 myotubes. AICAR also stimulated the level of FOXO transcription factors mRNA and protein in C2C12 myotubes. These results indicate that activation of AMPK stimulates myofibrillar protein degradation through the expression of atrogin-1/MAFbx and MuRF1 by increasing FOXO transcription factors in skeletal muscles.
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PMID:AMPK activation stimulates myofibrillar protein degradation and expression of atrophy-related ubiquitin ligases by increasing FOXO transcription factors in C2C12 myotubes. 1761 26

We examined the effects of orally administered glycine on myofibrillar proteolysis in food-deprived chicks. Food-deprived (24 h) chicks were orally administered 57, 113, and 225 mg glycine/100 g body weight and killed after 2 h. The plasma N(tau)-methylhistidine concentration, used as myofibrillar proteolysis, was decreased by glycine. We also examined the expression of proteolytic-related genes by real-time PCR of cDNA from chick skeletal muscles. The mRNA expression of atrogin-1/MAFbx, proteasome C2 subunit, m-calpain large subunit, and cathepsin B was decreased by glycine in a dose-dependent manner. The plasma corticosterone concentration was also decreased by glycine, but the plasma insulin concentration was unaffected. These results indicate that orally administered glycine suppresses myofibrillar proteolysis and expression of proteolytic-related genes of skeletal muscle by decreasing the plasma corticosterone concentration in chicks.
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PMID:Effects of orally administered glycine on myofibrillar proteolysis and expression of proteolytic-related genes of skeletal muscle in chicks. 1762 91

Unaccustomed exercise is known to produce strength loss, soreness, and myocellular disruption. With repeated application of exercise stimuli, the appearance of these indexes of muscle damage is attenuated, the so-called "repeated bout effect." No direct connection has been established between this repeated bout effect and exercise-induced increases in protein turnover, but it appears that a degree of tolerance is developed toward exercise for both. The present study sought to investigate markers of protein degradation by determining the expression of components related to the ubiquitin-proteasome system (UPS) with repeated exercise bouts. Healthy men carried out 30 min of bench stepping, performing eccentric work with one and concentric work with the other leg (n = 14), performing a duplicate exercise bout 8 wk later. A nonexercising control group was included (n = 6). RNA was extracted from muscle biopsies representing time points preexercise, +3 h, +24 h, and +7 days, and selected mRNA species were quantified using Northern blotting. The exercise model proved sufficient to produce a repeated bout effect in terms of strength and soreness. For forkhead box O transcription factor 1 (FOXO1) and muscle RING finger protein-1 (MURF1), strong upregulations were seen exclusively with concentric loading (P < 0.001), while atrogin-1 displayed a strong downregulation exclusively in response to eccentric exercise (P < 0.001). For MURF1 transcription, the first bout produced a downregulation that persisted until the second bout (P < 0.01). In conclusion, the UPS is modulated differentially in response to varying loading modalities and with different time frames in a way that to some extent reflects changes in protein metabolism known to take place with exercise.
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PMID:Expression patterns of atrogenic and ubiquitin proteasome component genes with exercise: effect of different loading patterns and repeated exercise bouts. 1769 Jan 90

Cachexia is a debilitating syndrome characterized by body weight loss, muscle wasting, and anemia. Muscle wasting results from an altered balance between protein synthesis and degradation rates. Reactive oxygen species are indicated as crucial players in the onset of muscle protein hypercatabolism by upregulating elements of the ubiquitin-proteasome pathway. The present study has been aimed at evaluating comparatively the involvement of oxidative stress in the pathogenesis of skeletal muscle wasting in two different experimental models: rats rendered hyperglycemic by treatment with streptozotocin and rats bearing the Yoshida AH-130 ascites hepatoma. For this purpose, both tumor bearers and diabetic animals have been treated with dehydroepiandrosterone (DHEA), a multifunctional steroid endowed with multitargeted antioxidant properties. We show that diabetic rats and AH-130 rats share several features, hypoinsulinemia, occurrence of oxidative stress, and positive response to DHEA administration, although the extent of the effects of DHEA largely differs between diabetic animals and tumor-bearing rats. The hypercatabolism, evaluated in terms of proteasome activity and expression of atrogin-1 and MuRF1, is activated in AH-130 rats, whereas it is lacking in streptozotocin-treated rats. Moreover, we demonstrate that the role of oxidative stress can interfere with muscle wasting through different mechanisms, not necessarily involving NF-kappaB activation. In conclusion, the present results show that, although skeletal muscle wasting occurs in both diabetic rats and tumor-host rats, the underlying mechanisms are different. Moreover, despite oxidative stress being detectable in both experimental models, its contribution to muscle wasting is not comparable.
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PMID:Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress. 1805 17


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