Mechanism of muscle protein degradation in cancer cachexia

Smith, K. L.; Tisdale, Michael J.

doi:10.1038/bjc.1993.334

Cited by 60 publications

(30 citation statements)

References 17 publications

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“…The mechanism for the loss of protein in gastrocnemius muscle at weight losses greater than 20% requires further investigation, but the lack of bioactivity of serum from mice bearing the MAC16 tumour at weight losses of 20 -25% (Smith and Tisdale, 1993b) suggests that a circulatory factor is not responsible for the protein degradation, and the present results suggest that the ubiquitinproteasome pathway alone cannot account for the high level of protein breakdown. This suggests that depression of protein synthesis may be more important than an increase in protein degradation at high weight loss. )…”

Section: Discussionmentioning

confidence: 78%

“…Using the release of tyrosine as a measure of muscle protein degradation breakdown to detect serum factors from the MAC16 tumour that increase protein degradation, activity was found to increase with increasing weight loss up to 20%, and with further weight loss the activity was found to fall to a value not significantly different from that found in animals without weight loss (Smith and Tisdale, 1993b). This circulatory factor has now been isolated and identified (Todorov et al, 1996) and shown to be a sulphated glycoprotein of M r 24 kDa called proteolysis factor (PIF), which induces an increased expression of both proteasome subunits and E2 in gastrocnemius muscle (Lorite et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…We have previously shown a rise in the PGE2 level of gastrocnemius muscle after incubation with serum from cachectic mice bearing the MAC16 tumour, conditions that lead to an elevated protein degradation (Smith and Tisdale, 1993b). Induction of muscle protein degradation by the proteolysis-inducing factor was also associated with a rise in muscle PGE2 production.…”

Section: Discussionmentioning

confidence: 96%

“…The material was capable of direct induction of protein degradation in isolated soleus muscle as measured by tryrosine release (Figure 1). High concentrations of the material were inhibitory to protein degradation, resulting in a bell-shaped dose-response curve similar to that observed with serum from mice bearing the MAC 16 tumour and increasing weight loss (Smith and Tisdale, 1993b). To determine the pharmacokinetics of the material of apparent molecular weight 24 000 before in vivo administration, HPLCpurified antigen was labelled with 1251 and the labelled material was administered i.v.…”

Section: Prostaglandin E2 Determinationmentioning

confidence: 99%

Induction of muscle protein degradation by a tumour factor

Lorite

Cariuk²,

Tisdale³

1997

Br J Cancer

Self Cite

116

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Summary An antigen of apparent molecular weight of 24000, reactive with a murine monoclonal antibody, has been isolated from a cachexia-inducing tumour (MAC 16) and has been shown to initiate muscle protein degradation in vitro using isolated soleus muscle. Administration of this material to female NMRI mice (20 g) produced a pronounced depression in body weight (2.72 ± 0.14 g; P<0.005 from control) over a 24 h period. This weight loss was attenuated in mice pretreated with the monoclonal antibody (0.06 + 0.26 g over 24 h) and occurred without a reduction in food and water intake. There was no change in body water composition, and the major contribution to the decrease in body weight was a decrease in the non-fat carcass dry weight (mainly lean body mass). The plasma levels of glucose and most amino acids were also significantly depressed. The decrease in lean body mass was accounted for by an increase (by 50%) in protein degradation and a decrease (by 50%) in protein synthesis in gastrocnemius muscle. Protein degradation was significantly decreased and protein synthesis increased to control values in mice pretreated with the monoclonal antibody. Protein degradation initiated in vitro with the proteolysis-inducing factor was abolished in mice pretreated with eicosapentaenoic acid (EPA), which had been shown to prevent muscle wastage in mice bearing the MAC16 tumour. Protein degradation was associated with a significant elevation of prostaglandin E2 production by isolated soleus muscle, which was inhibited by both the monoclonal antibody and EPA. These results suggest that this material may be the humoral factor mediating changes in skeletal muscle protein homeostasis during the process of cancer cachexia in animals bearing the MAC16 tumour, and could potentially be involved in other cases of cachexia.

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“…GAS was removed for measurement of protein metabolism, as described previously (41). Briefly, muscles were preincubated for 15 min in Krebs-Henseleit buffer and then transferred to fresh medium of the same composition containing 0.1% bovine serum albumin (99% fatty acid free) and 0.5 mmol/l L-U[…”

Section: Protein Synthesis and Proteolysis Measurementsmentioning

confidence: 99%

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

Britto

Begue

Rossano

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

103

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Ferry A, Bonnieu A, Ollendorff V, Favier FB. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 307: E983-E993, 2014. First published October 14, 2014 doi:10.1152/ajpendo.00234.2014.-REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wildtype (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoidinduced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy. regulated in development and DNA damage response 1; protein synthesis; mechanistic target of rapamycin; autophagy; glucocorticoids; proline-rich Akt substrate of 40 kDa

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Mechanism of muscle protein degradation in cancer cachexia

Cited by 60 publications

References 17 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

Induction of muscle protein degradation by a tumour factor

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

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