Weight loss in a murine cachexia model is not associated with the cytokines tumour necrosis factor-α or interleukin-6

Mulligan, H. D.; Mahony, S. M.; Ross, James A.; Tisdale, Michael J.

doi:10.1016/0304-3835(92)90238-q

Cited by 22 publications

(9 citation statements)

References 20 publications

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“…However. our previous studies (Mulligan et al 1992) have failed to find anv evidence for an involvement of either TNT-a or IL-6 in the process of cachexia induced by the MAC 16 tumour. suggestinc that PIF may be directly involved.…”

Section: Resultsmentioning

confidence: 87%

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Lorite

Thompson²,

Drake³

et al. 1998

Br J Cancer

122

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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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Section: Resultsmentioning

confidence: 87%

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Lorite

Thompson²,

Drake³

et al. 1998

Br J Cancer

122

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“…Ang II directly stimulates tumour necrosis factor-a (TNF-a) and interleukin-6 (IL-6) production in human peripheral monocytes and ACE inhibitors inhibit LPS-induced TNF-a production (Peeters et al, 1998). However, the activity of imidapril in the MAC16 model could not be explained by an effect on TNF-a or IL-6 production, since we have previously shown no involvement of these cytokines in the cachectic process in this model (Mulligan et al, 1992).…”

Section: Discussionmentioning

confidence: 95%

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

2005

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The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose -response curve and with a maximal effect between 0.05 and 0.1 mM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose -response curve, and with a maximal effect between 1 and 2.5 mM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 mM) and MG132 (10 mM), suggesting that the effect was mediated through upregulation of the ubiquitin -proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome a-subunits, the 19S subunits MSS1 and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin -proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitort) (30 mg kg À1 ) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model.

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“…The only other potential mediator of the increased ZAG expression in cachexia is interferon-g (IFNg), which has been shown to strongly upregulate expression in human epithelial cell lines (Brysk et al, 1997), and has been suggested to be responsible for the development of cachexia in the Lewis lung tumour model (Matthys et al, 1991b). However, cachexia in mice bearing the MAC16 tumour is not thought to be cytokine mediated (Mulligan et al, 1992), and is not associated with the development of anorexia seen in mice inoculated with CHO cells transfected with the IFNg gene (Matthys et al, 1991a).…”

Section: Discussionmentioning

confidence: 99%

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

Russell

Tisdale

2005

Br J Cancer

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Loss of adipose tissue in cancer cachexia in mice bearing the MAC16 tumour arises from an increased lipid mobilisation through increased expression of zinc-a 2 -glycoprotein (ZAG) in white (WAT) and brown (BAT) adipose tissue. Glucocorticoids have been suggested to increase ZAG expression, and this study examines their role in cachexia and the mechanisms involved. In mice bearing the MAC16 tumour, serum cortisol concentrations increased in parallel with weight loss, and the glucocorticoid receptor antagonist RU38486 (25 mg kg À1 ) attenuated both the loss of body weight and ZAG expression in WAT. Dexamethasone (66 mg kg À1 ) administration to normal mice produced a six-fold increase in ZAG expression in both WAT and BAT, which was also attenuated by RU38486. In vitro studies using 3T3-L1 adipocytes showed dexamethasone (1.68 mM) to stimulate lipolysis and increase ZAG expression, and both were attenuated by RU38486 (10 mM), anti-ZAG antibody (1 mgml À1 ), and the b3-adrenoreceptor (b3-AR) antagonist SR59230A (10 mM). Zinc-a 2 -glycoprotein also increased its own expression and this was attenuated by SR59230A, suggesting that it was mediated through the b3-AR. This suggests that glucocorticoids stimulate lipolysis through an increase in ZAG expression, and that they are responsible for the increase in ZAG expression seen in adipose tissue of cachectic mice.

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Weight loss in a murine cachexia model is not associated with the cytokines tumour necrosis factor-α or interleukin-6

Cited by 22 publications

References 20 publications

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

The role of glucocorticoids in the induction of zinc-α2-glycoprotein expression in adipose tissue in cancer cachexia

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