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Schematic representation of the breakdown of myofibrillar proteins. The ubiquitination enzymes, ubiquitin (Ub)-activating enzyme (E1), Ub-conjugating enzymes (E2) and Ub-protein ligases (E3), tag disassembled myofibrillar proteins with a polyUb degradation signal. The polyUb chain binds to the 19S complex (19S) of the 26S proteasome. ATPases within 19S provide energy for the recognition of the polyUb degradation signal, unfolding of the substrate, the gating of the 20S proteasome (20S) channel, the injection and progression of the substrate into the catalytic chamber of the 20S proteasome, protein hydrolysis and peptide release. ( ), The b catalytic subunits of the 20S proteasome; ( ), the a non-catalytic subunits of the 20S proteasome. The polyUb chain is recycled into free Ub by the deubiquitinating activity intrinsic to the 19S complex and/or deubiquitinating enzymes (DUB). The final hydrolysis of the peptides generated by the 26S proteasome into free amino acids is then sequentially performed by the tripeptidyl peptidase II (TPP II) and exopeptidases.
Source publication
In skeletal muscle, as in any mammalian tissue, protein levels are dictated by relative rates of protein synthesis and breakdown. Recent studies have shown that the ubiquitin-proteasome-dependent proteolytic pathway is mainly responsible for the breakdown of myofibrillar proteins. In this pathway proteins that are to be degraded are first tagged wi...
Contexts in source publication
Context 1
... protein sorting and the control of transcrip- tion and of cell division (Glickman & Ciechanover, 2002). Basically, there are two main steps in the pathway: (1) covalent attachment of a polyUb chain to the substrate; (2) specific recognition of the polyUb degradation signal and subsequent breakdown of the targeted protein by the 26S proteasome (Fig. ...
Context 2
... The putative roles of deubiquitinating enzymes in proteasome-dependent proteolysis are: (1) to maintain free Ub levels by processing polyUb degradation signals and Ub precursors into free monomers; (2) to proof-read and deubiquitinate substrates erroneously tagged for degradation; (3) to keep 26S proteasomes free of bound-polyUb chains ( Fig. 1; Attaix et al. ...
Context 3
... second major step in the Ub-proteasome pathway is the degradation of polyubiquitinated proteins by the 26S proteasome complex. The 26S proteasome is formed by the association of the 20S proteasome with two 19S regulatory complexes ( Fig. 1; for review, see Glickman & Ciechanover, 2002;Attaix et al. 2003). The 20S protea- some is the core of the proteolytic machinery. This barrel- shaped particle is organised as a stack of four rings, each ring containing seven subunits (Fig. 1). The non-catalytic a-subunits form the two outer rings and the catalytic b-subunits form the ...
Context 4
... The 26S proteasome is formed by the association of the 20S proteasome with two 19S regulatory complexes ( Fig. 1; for review, see Glickman & Ciechanover, 2002;Attaix et al. 2003). The 20S protea- some is the core of the proteolytic machinery. This barrel- shaped particle is organised as a stack of four rings, each ring containing seven subunits (Fig. 1). The non-catalytic a-subunits form the two outer rings and the catalytic b-subunits form the two inner rings. The b-subunit active sites are located inside the cylinder and thus the protea- some is a self-compartmentalising protease, as substrates must enter the catalytic chamber delimited by the b-rings to be degraded into peptides. ...
Context 5
... outer a-rings of the 20S proteasome. They contain at least six ATPase and twelve non-ATPase subunits. The ATPase subunits provide energy for assem- bly of the 26S proteasome, gating of the 20S proteasome channel, unfolding and injection of protein substrates into the catalytic chamber of the proteasome, proteolysis and energy for peptide release (Fig. 1). Both the non-ATPase subunit S5a and the ATPase S6k subunit bind to polyUb chains and the latter interaction also depends on ATP hydrolysis (for review, see Attaix et al. ...
Context 6
... pointed out that other proteolytic enzymes also play a role in these processes. For example, the 26S proteasome degrades proteins only into peptides, which must undergo further hydrolysis into free amino acids. The extralysosomal tripeptidyl-peptidase II and then exopeptidases degrade peptides generated by the protea- some into free amino acids ( Fig. 1; Hasselgren et al. 2002). Conversely, other proteinases may act upstream of the proteasome. The rate-limiting step in the breakdown of myofibrillar proteins is probably their dissociation from the myofibril, since specific interactions protect them from Ub-dependent degradation (Solomon & Goldberg, 1996). Calpains play key roles in the ...
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The modification of proteins by chains of ubiquitin has long been known to mediate targeting of cytosolic and nuclear proteins for degradation by proteasomes. In this article, we discuss recent developments that reveal the involvement of ubiquitin in the degradation of proteins retained within the endoplasmic reticulum (ER) and in the internalizati...
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Citations
... Interestingly, physical activity increases humanin in plasma [48]. Humanin can be destabilized via ubiquitination assisted by TRIM11 [49], a process that could be interrupted by aerobic exercise, which inhibits the ubiquitin-proteosome pathway [50]. In turn, increased humanin levels could inhibit the pro-apoptotic factors BAX and BID, thus preventing mitochondrial-outer membrane permeabilization and enhancing neuronal survival and cognitive performance in AD [51]. ...
Background
Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for the effects of exercise in Alzheimer’s disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF, and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX.
Methods
proBDNF, BDNF, and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, and collected at baseline and 16 weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues.
Results
NDEV levels of proBDNF, BDNF, and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged.
Conclusions
Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders.
Trial registration
The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered in ClinicalTrials.gov on April 30, 2012 with the identifier NCT01681602.
Graphical abstract
... In the ubiquitin-proteasome pathway, a chain of ubiquitin molecules is covalently attached to target proteins by ubiquitin ligases, leading to their degradation by the 26S proteasome 18 . An increase in the concentration of polyubiquitinated proteins is considered a useful marker for accelerated muscle proteolysis via the ubiquitin-proteasome pathway 26 . ...
... The increased rate of MPB is also considered a major cause of energy restriction-induced loss of skeletal muscle. The ubiquitin-proteasome pathway is one of the major protein degradation pathways in the skeletal muscle 18 . Polyubiquitinated protein concentration, a marker of protein degradation by the ubiquitin-proteasome pathway, has been reported to increase in fast-twitch skeletal muscles during energy restriction 26 . ...
Dietary intake of medium-chain triacylglycerols (MCTs) is known to alleviate obesity. MCTs have also been suggested to beneficially influence protein metabolism. This study evaluated the effects of dietary intake of MCTs on energy restriction-induced weight control and loss of skeletal muscle. Rats were divided into the following groups: 1) AL-LCT group that received the AIN-93G-based control diet containing long-chain triacylglycerols (LCTs) ad libitum, 2) ER-LCT group fed the control diet with 30% energy restriction, and 3) ER-MCT group fed a diet containing MCTs with 30% energy restriction. After the 4-wk dietary treatment, both energy-restricted groups had significantly lower body weight than the AL-LCT group and rats in the ER-MCT group were significantly lighter than those in the ER-LCT group. In contrast, the extent of energy restriction-induced loss of skeletal muscle was not significantly different between the two energy-restricted groups, resulting in an increase in muscle mass relative to body weight in the ER-MCT group. Despite maintaining the lower body weight, dietary intake of MCTs did not further influence signaling pathways involved in protein synthesis or breakdown. These results suggest that intake of MCTs could be a valuable dietary intervention to maintain a lower body weight and increase relative muscle mass without negative effects on skeletal muscle protein metabolism.
graphical abstract Fullsize Image
... Interestingly, physical activity increases humanin in plasma (48). Humanin can be destabilized via ubiquitination assisted by TRIM11 (49), a process that could be interrupted by aerobic exercise, which inhibits the ubiquitin-proteosome pathway (50). In turn, increased humanin levels could inhibit the pro-apoptotic factors BAX and BID, thus preventing mitochondrial-outer membrane permeabilization and enhancing neuronal survival and cognitive performance in AD (51). ...
Background
Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for effects of exercise in Alzheimer’s disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX.
Methods
proBDNF, BDNF and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, collected at baseline and 16-weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues.
Results
NDEV levels of proBDNF, BDNF and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged.
Conclusions
Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders.
Trial registration
The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered as ClinicalTrials.gov Identifier: NCT01681602 and was first submitted on April 30, 2012 and was first submitted that met QC criteria on September 5, 2012.
... In addition, it has been demonstrated that mafbx interacts with myod regulating its expression; therefore, in this study mafbx might be inhibiting myod expression prematurely at day 8 in order to ensure the correct activity of Mrfs from day 16 onwards (59). In summary, some of these proteolytic genes could be necessary in our study species, to modulate myogenesis, as observed previously in mammals (60). Thus, these genes could be involved in myoblast proliferation and differentiation (61, 62) but are also required for myoblast fusion (63, 64). ...
Fish muscle regeneration is still a poorly known process. In the present study, an injury was done into the left anterior epaxial skeletal muscle of seventy 15 g gilthead sea bream (Sparus aurata) juveniles to evaluate at days 0, 1, 2, 4, 8, 16 and 30 post-wound, the expression of several muscle genes. Moreover, transcripts’ expression in the bone (uninjured tissue) was also analyzed. Histology of the muscle showed the presence of dead tissue the first day after injury and how the damaged fibers were removed and replaced by new muscle fibers by day 16 that kept growing up to day 30. Gene expression results showed in muscle an early upregulation of igf-2 and a downregulation of ghr-1 and igf-1. Proteolytic systems expression increased with capn2 and ctsl peaking at 1 and 2 days post-injury, respectively and mafbx at day 8. A pattern of expression that fitted well with active myogenesis progression 16 days after the injury was then observed, with the recovery of igf-1, pax7, cmet, and cav1 expression; and later on, that of cav3 as well. Furthermore, the first days post-injury, the cytokines il-6 and il-15 were also upregulated confirming the tissue inflammation, while tnfα was only upregulated at days 16 and 30 to induce satellite cells recruitment; overall suggesting a possible role for these molecules as myokines. The results of the bone transcripts showed an upregulation first, of bmp2 and ctsk at days 1 and 2, respectively; then, ogn1 and ocn peaked at day 4 in parallel to mstn2 downregulation, and runx2 and ogn2 increased after 8 days of muscle injury, suggesting a possible tissue crosstalk during the regenerative process. Overall, the present model allows studying the sequential involvement of different regulatory molecules during muscle regeneration, as well as the potential relationship between muscle and other tissues such as bone to control musculoskeletal development and growth, pointing out an interesting new line of research in this group of vertebrates.
... Ubiquitin is covalently attached to lysine residues that can be a proteolytic or nonproteolytic signal depending on the number and linkage of the ubiquitin molecules. 1 The addition of 4 or more ubiquitin molecules linked via lysine 48, resulting in a polyubiquitin chain, typically targets a protein for degradation by the 26S proteasome. The specificity of ubiquitination is determined by the E3 ligase, which brings together an E2 enzyme and a substrate protein through protein-protein interaction domains or adaptor proteins that recruit the substrate protein. ...
MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine if MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere, but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.
... Myofibril loss, also referred to as sarcopenia, becomes further exacerbated when patients suffer from additional cachexia-promoting states, such as diabetes, sepsis, or inflammation, that further promote general muscle catabolism [3,4]. The molecular mechanisms that underlie the development of muscle wasting include downregulation of the translation of muscle proteins, activation of their degradation by site-specific proteases such as cathepsin D and calpains (for review, [5]), or by autophagosomes (linked to ATG modification; for review, [6]) and activation of the ubiquitin-proteasome system (UPS; linking multiubiquitination to proteolysis; for review, see [7]). Activation of the UPS is induced in stressed muscles by specific atrogenes that function as ubiquitin E3 ligases to multiubiquitinate muscle proteins, thereby subjecting them to proteasome-dependent degradation [8][9][10]. ...
The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte–granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions.
... Exercise training was found to reduce SLC8A1 expression in animals susceptible to heart diseases [32] and SLC8A1 was associated with hand grip strength and bone density [17,33]. Exercise training was also found in mice to affect ubiquitin-proteasome systems [34], which has a role in skeletal muscle remodeling during exercise [35]. As skeletal muscle and muscle strength could influence bone strength [36], exercise might influence SLC8A1 expression and interact with SEM1 to affect ubiquitin-proteasome systems to further affect bone density. ...
Background
Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study.
Methods
Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD.
Results
We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD ( p < 0.05). Higher PRS was associated with a lower total body BMD (β = − 0.040 ± 0.009, p = 1.1 × 10 − 5 ) and lumbar spine BMD (β = − 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (β = − 0.015 ± 0.006, p = 0.02; β = 0.008 ± 0.01, p = 0.4, respectively).
Discussion
The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed.
Conclusions
Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.
... In addition, CoQ10 is mainly carried by LDL cholesterol, thus the lowering of LDL cholesterols lowers CoQ10. Coenzyme Q is responsible for remodeling skeletal muscle and functions in electron transport chain of the mitochondria in producing ATP, decreases under statin therapy (16). However, studies that supplement Coenzyme Q for patients with myalgia show little to no effects on pain management (17). ...
Statins are widely prescribed and used chronically, but we know little about the effects on long-term protein homeostasis during stress and aging. Our aim was to quantify the effect of statins on stress-induced protein damage. We administered atorvastatin in a dose-response curve in Caenorhabditis elegans under naïve control conditions and in conditions of hypertonic and heat stress known to induce muscle damage measurable as countable puncta in a polyglutamine aggregation model of damage. We observed that there is significant polyglutamine aggregation variability among worms at baseline and thus further study requires within experiment baseline controls, per worm. Our results are that statins exacerbate (p
... Muscle weakness can be attributed, in part, to muscle fiber atrophy that results from enhanced proteolysis (13). On the other hand, protein breakdown is a necessary mechanism to maintain proteostasis and myocyte survival (2,51). The main proteolytic pathways in skeletal muscle are the calpain, caspase, ubiquitin-proteasome, and autophagylysosome pathways (Fig. 1). ...
An impaired capacity of muscle to regenerate after critical illness results in long-term functional disability. We previously described in a long-term rat peritonitis model that gastrocnemius displays near-normal histology whereas soleus demonstrates a necrotizing phenotype. We thus investigated the link between the necrotizing phenotype of critical illness myopathy and proteasome activity in these two limb muscles. We studied male Wistar rats that underwent an intraperitoneal injection of the fungal cell wall constituent, zymosan, or n-saline as a sham-treated control. Rats (n=74) were killed at 2, 7, and 14 days post-intervention with gastrocnemius and soleus muscle removed and studied ex vivo. Zymosan-treated animals displayed an initial reduction of body weight, but a persistent decrease in mass of both lower hind-limb muscles. Zymosan increased chymotrypsin- and trypsin-like proteasome activities in gastrocnemius at days 2 and 7, but in soleus at day 2 only. Activated caspases 3 and 9, polyubiquitin proteins and 14kDa fragments of myofibrillar actin (proteasome substrates) remained persistently increased from day 2 to day 14 in soleus, but not in gastrocnemius. These results suggest that a relative proteasome deficiency in soleus is associated with a necrotizing phenotype during long-term critical illness. Rescuing proteasome clearance may offer a potential therapeutic option to prevent long-term functional disability in critically ill patients.
... TNFa and IL-6) and NF-κB signalling (15,16) . However, following EIMD, both proteasome-and immunoproteasome-mediated proteolysis promote degradation of damaged and/or unfolding proteins and facilitate myogenesis and recovery of muscle's functional capacity (17,18) . Indeed, marked elevation in mRNA and protein expression level of specific E3 ubiquitin ligases persists up to 48 h following a single bout of eccentric exercise (19) . ...
... To the best of our knowledge, this is the first study examining the responses of β-subunits, βi-subunits (related to the immunoproteasome) and their activities to aseptic inflammation induced by extremely damaging exercise and in combination with protein supplementation. Although the UPS proteolytic pathway is upregulated under inflammatory conditions (50,51) , it seems that it contributes to the remodelling of skeletal muscle following muscle injury induced by exercise (18) . In previous studies, both mRNA and protein levels of ubiquitin ligases (MuRF1 and MAFbx/Atrogin-1) and the 20S proteasome have been repeatedly shown to be upregulated following eccentric exercise for as long as 24-48 h (43,45,52) . ...
... In previous studies, both mRNA and protein levels of ubiquitin ligases (MuRF1 and MAFbx/Atrogin-1) and the 20S proteasome have been repeatedly shown to be upregulated following eccentric exercise for as long as 24-48 h (43,45,52) . Moreover, increased CT-L activity has been observed at 14 d following downhill running (53) , further supporting the fundamental role of UPS in skeletal muscle remodelling (18,19) . In contrast, we observed a 30 % decrease in CT-L activity at 2 d post exercise that was not accompanied by any change in protein levels of 20S proteasome and immunoproteasome β-subunits and βi-subunits, respectively. ...
The ubiquitin–proteasome system (UPS) is the main cellular proteolytic system responsible for the degradation of normal and abnormal (e.g. oxidised) proteins. Under catabolic conditions characterised by chronic inflammation, the UPS is activated resulting in proteolysis, muscle wasting and impaired muscle function. Milk proteins provide sulphur-containing amino acid and have been proposed to affect muscle inflammation. However, the response of the UPS to aseptic inflammation and protein supplementation is largely unknown. The aim of this study was to investigate how milk protein supplementation affects UPS activity and skeletal muscle function under conditions of aseptic injury induced by intense, eccentric exercise. In a double-blind, cross-over, repeated measures design, eleven men received either placebo (PLA) or milk protein concentrate (PRO, 4×20 g on exercise day and 20 g/d for the following 8 days), following an acute bout of eccentric exercise (twenty sets of fifteen eccentric contractions at 30°/s) on an isokinetic dynamometer. In each trial, muscle biopsies were obtained from the vastus lateralis muscle at baseline, as well as at 2 and 8 d post exercise, whereas blood samples were collected before exercise and at 6 h, 1 d, 2 d and 8 d post exercise. Muscle strength and soreness were assessed before exercise, 6 h post exercise and then daily for 8 consecutive days. PRO preserved chymotrypsin-like activity and attenuated the decrease of strength, facilitating its recovery. PRO also prevented the increase of NF- κ B phosphorylation and HSP70 expression throughout recovery. We conclude that milk PRO supplementation following exercise-induced muscle trauma preserves proteasome activity and attenuates strength decline during the pro-inflammatory phase.
