TNF Can Directly Induce the Expression of Ubiquitin-Dependent Proteolytic System in Rat Soleus Muscles

Llovera, Marta; Garcı́a-Martı́nez, Cèlia; Agell, Neus; López‐Soriano, Francisco J.; Argilés, Josep Μ.

doi:10.1006/bbrc.1996.5827

Cited by 162 publications

(95 citation statements)

References 31 publications

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“…Loss of skeletal muscle mass arises from a reduction (by 60%) in protein synthesis and an increase (three-fold) in protein degradation (Beck et al, 1991). As was found in a rat model of cancer cachexia (Baracos et al, 1995;Llovera et al, 1997), the major contribution to the loss of muscle mass in mice bearing the MAC16 tumour appears to arise from an upregulation of the ATPubiquitin-dependent proteolytic pathway (Lorite et al, 1998), as reflected by increased levels of ubiquitin-conjugated proteins and increased mRNA levels for the 14 kDa ubiquitin carrier protein, E2 and the C9 proteasome subunit in gastrocnemius muscle. However, as with other studies in animals this was only measured after weight loss had developed, and there have been no measurements of the expression of the major components of the ubiquitin-proteasome pathway at different extents of weight loss, or a comparison between different muscle types to understand if this pathway totally explains protein degradation.…”

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confidence: 60%

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

et al. 2005

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Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2 14k , has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2 14k were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2 14k mRNA and protein levels in gastrocnemius muscle with increases of 6 -8-fold for C2 and two-fold for E2 14k between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25 -27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18 -20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2 14k mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss.

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confidence: 60%

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

et al. 2005

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“…In addition we have chosen to measure E2 14k and 20S/19S proteasome expression as a measure of the ubiquitin-proteasome pathway, rather than changes in ubiquitin expression and conjugation, because an increase in ubiquitin may signal an increased cell death through apoptosis (Soldatenkov and Dritschilo, 1997), rather than an increase in proteolysis. Thus, although the enhanced protein degradation in rat skeletal muscle in vivo after TNF-a administration is associated with an increase in gene transcription, and higher levels of free and conjugated ubiquitin (Garcia-Martinez et al, 1993), there is no evidence for an increase in proteasome expression in vitro (Ebisui et al, 1995), although an increased ubiquitin gene expression was still observed (Llovera et al, 1997). In the muscles of mice bearing the colon 26 tumour loss of muscle mass was associated with an increase in expression of both polyubiquitin and proteasome subunits.…”

Section: Discussionmentioning

confidence: 89%

Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor

et al. 2002

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The mechanism of muscle protein catabolism induced by proteolysis-inducing factor, produced by cachexia-inducing murine and human tumours has been studied in vitro using C 2 C 12 myoblasts and myotubes. In both myoblasts and myotubes protein degradation was enhanced by proteolysis-inducing factor after 24 h incubation. In myoblasts this followed a bell-shaped doseresponse curve with maximal effects at a proteolysis-inducing factor concentration between 2 and 4 nM, while in myotubes increased protein degradation was seen at all concentrations of proteolysis-inducing factor up to 10 nM, again with a maximum of 4 nM proteolysis-inducing factor. Protein degradation induced by proteolysis-inducing factor was completely attenuated in the presence of cycloheximide (1 mM), suggesting a requirement for new protein synthesis. In both myoblasts and myotubes protein degradation was accompanied by an increased expression of the a-type subunits of the 20S proteasome as well as functional activity of the proteasome, as determined by the 'chymotrypsin-like' enzyme activity. There was also an increased expression of the 19S regulatory complex as well as the ubiquitin-conjugating enzyme (E2 14k ), and in myotubes a decrease in myosin expression was seen with increasing concentrations of proteolysis-inducing factor. These results show that proteolysisinducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia.

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“…although there was no change in the expression of the C8 proteasome subunit. which may require a longer time interval for induction (Llovera et al 1997). IL-6 has also been found to increase the activity of the 26S proteasome in murine C2C, myotubes in vitro (Ebisui et al 1995).…”

Section: Resultsmentioning

confidence: 99%

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Lorite

Thompson²,

Drake³

et al. 1998

Br J Cancer

121

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Summary A proteolysis-inducing factor (PIF) isolated from a cachexia-inducing murne tumour (MAC16) produced a decrease in body weight (1.6 g, P. 0.01 compared with control subjects) within 24 h after i.v. administration to non-tumour-bearing mice. Weight loss was associated with significant decreases in the weight of the spleen and soleus and gastrocnemius muscles. with no effect on the weight of the heart or kidney and with an increase in weight of the liver. Protein degradation in isolated soleus muscle was signfficantly increased in mice bearing the MAC16 tumour. To define which proteolytic pathways contribute to this increase, soleus muscles from mice bearing the MAC16 tumour and non-tumour-bearing animals administered PIF were incubated under conditions that modify different proteolytic systems. In mice bearing the MAC16 tumour, there were increases in both cathepsin B and L, and the Ca2--dependent lysosomal and ATP-dependent pathways were found to contribute to the increased proteolysis; whereas, in PIF-injected animals, there was activation only of the ATP-dependent pathway. Further studies in mice bearing the MAC16 tumour have provided evidence for increased levels of ubiquitin-conjugated proteins and increased mRNA levels for the 14 kDa ubiquitin carrier protein E2 and the C9 proteasome subunit in gastrocnemius muscle, suggesting activation of the ATP-ubiquitin-dependent proteolytic pathway. A monoclonal antibody to PIF attenuated the enhanced protein degradation in soleus muscle from mice bearing the MAC16 tumour, confirming that PIF is responsible for the loss of skeletal muscle in cachectic mice.

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TNF Can Directly Induce the Expression of Ubiquitin-Dependent Proteolytic System in Rat Soleus Muscles

Cited by 162 publications

References 31 publications

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor

Mechanism of muscle protein degradation induced by a cancer cachectic factor

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