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Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium.

Wang H, Li TL, Hsia S, Su IL, Chan YL, Wu CJ - Oncotarget (2015)

Bottom Line: In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation.In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy.The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan.

ABSTRACT
Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.

No MeSH data available.


Related in: MedlinePlus

Effects of daily oral administration of background diet or combined nutritional components (addition of fish oil (fo) or selenium yeast (se)) on skeletal muscle atrophy in tumor-bearing mice with chemotherapy (protocol #3)(A) differences in soleus and gastrocnemius weights at day 42 after intervention with nutritional supplements in tumor-bearing mice after chemotherapy. (B) Effects of serum from mice on P19 cell growth. Serum (10% of assay volume) was added to the P19 cell line, and the cell viability during 24 hours incubation was determined by the MTS assay. (C) Concentrations of plasma phospholipids [16] fatty acids in mice. (D) Western blots analysis for expressions of IL-6, TNF-α and myostatin in gastrocnemius muscles of mice (left). Protein levels for ubiquitin ligases, FoxO-1, cathepsin L and calpain in gastrocnemius muscle during cancer and chemotherapy (right). (E) The model illustration for fish oil plus selenium attenuated muscle atrophy after chemotherapy. Under chemotherapy, tumor-bearing mice exhibited a significant increase in the expression of myostatin that activates FoxO-1, and leads to up-regulation of proteasome ubiquitin ligases MuRF-1 and MAFbX. Con, normal control mice; TD, tumor-bearing mice receiving docetaxel; TD-base, tumor-bearing mice receiving docetaxel and background diet; TD-fo+se, tumor bearing mice receiving background diet with additional fish oil and selenium yeast. Data are shown as mean ± SD. n = 5–9 mice/group and each value is an average of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 denote levels of significant differences between groups.
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Figure 5: Effects of daily oral administration of background diet or combined nutritional components (addition of fish oil (fo) or selenium yeast (se)) on skeletal muscle atrophy in tumor-bearing mice with chemotherapy (protocol #3)(A) differences in soleus and gastrocnemius weights at day 42 after intervention with nutritional supplements in tumor-bearing mice after chemotherapy. (B) Effects of serum from mice on P19 cell growth. Serum (10% of assay volume) was added to the P19 cell line, and the cell viability during 24 hours incubation was determined by the MTS assay. (C) Concentrations of plasma phospholipids [16] fatty acids in mice. (D) Western blots analysis for expressions of IL-6, TNF-α and myostatin in gastrocnemius muscles of mice (left). Protein levels for ubiquitin ligases, FoxO-1, cathepsin L and calpain in gastrocnemius muscle during cancer and chemotherapy (right). (E) The model illustration for fish oil plus selenium attenuated muscle atrophy after chemotherapy. Under chemotherapy, tumor-bearing mice exhibited a significant increase in the expression of myostatin that activates FoxO-1, and leads to up-regulation of proteasome ubiquitin ligases MuRF-1 and MAFbX. Con, normal control mice; TD, tumor-bearing mice receiving docetaxel; TD-base, tumor-bearing mice receiving docetaxel and background diet; TD-fo+se, tumor bearing mice receiving background diet with additional fish oil and selenium yeast. Data are shown as mean ± SD. n = 5–9 mice/group and each value is an average of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 denote levels of significant differences between groups.

Mentions: It has been known that myostatin up-regulates the genes involved in the ubiquitin-mediated proteolysis through the NF-κB-independent, FoxO1-dependent mechanism [31]. The FoxO-1 transcription factors can induce skeletal muscle wasting via regulating the atrophy-related genes, namely, the ubiquitin ligase MAFbX and Cathepsin-L [32, 33]. The mRNA and protein levels of FoxO-1 markedly increased in both moderate and severe cachectic mice (Figure 3B). Though FoxO-1 is related to lysosomal atrophy, the mRNA level of cathepsin-L only slightly increased in our experiment (Figure 3B). To confirm that the tumor-induced muscle atrophy truly follows the ubiquitin-proteasome pathway, the expression of ubiquitin ligases was examined by indirect immunofluorescence assay. As shown in Figure 3B and C, the protein levels of MAFbX and MuRF-1 increase in the gastrocnemius muscle of the tumor-bearing mice. Taken together, the tumor-induced muscle atrophy is likely due to elevated levels of TNF-α and myostatin, which act together to activate NF-κB and FoxO1 so as to amplify the expressions of calpain (autolysis) and ubiquitin ligases (ubiquitin-proteasome) (Figure 5E).


Skeletal muscle atrophy is attenuated in tumor-bearing mice under chemotherapy by treatment with fish oil and selenium.

Wang H, Li TL, Hsia S, Su IL, Chan YL, Wu CJ - Oncotarget (2015)

Effects of daily oral administration of background diet or combined nutritional components (addition of fish oil (fo) or selenium yeast (se)) on skeletal muscle atrophy in tumor-bearing mice with chemotherapy (protocol #3)(A) differences in soleus and gastrocnemius weights at day 42 after intervention with nutritional supplements in tumor-bearing mice after chemotherapy. (B) Effects of serum from mice on P19 cell growth. Serum (10% of assay volume) was added to the P19 cell line, and the cell viability during 24 hours incubation was determined by the MTS assay. (C) Concentrations of plasma phospholipids [16] fatty acids in mice. (D) Western blots analysis for expressions of IL-6, TNF-α and myostatin in gastrocnemius muscles of mice (left). Protein levels for ubiquitin ligases, FoxO-1, cathepsin L and calpain in gastrocnemius muscle during cancer and chemotherapy (right). (E) The model illustration for fish oil plus selenium attenuated muscle atrophy after chemotherapy. Under chemotherapy, tumor-bearing mice exhibited a significant increase in the expression of myostatin that activates FoxO-1, and leads to up-regulation of proteasome ubiquitin ligases MuRF-1 and MAFbX. Con, normal control mice; TD, tumor-bearing mice receiving docetaxel; TD-base, tumor-bearing mice receiving docetaxel and background diet; TD-fo+se, tumor bearing mice receiving background diet with additional fish oil and selenium yeast. Data are shown as mean ± SD. n = 5–9 mice/group and each value is an average of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 denote levels of significant differences between groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 5: Effects of daily oral administration of background diet or combined nutritional components (addition of fish oil (fo) or selenium yeast (se)) on skeletal muscle atrophy in tumor-bearing mice with chemotherapy (protocol #3)(A) differences in soleus and gastrocnemius weights at day 42 after intervention with nutritional supplements in tumor-bearing mice after chemotherapy. (B) Effects of serum from mice on P19 cell growth. Serum (10% of assay volume) was added to the P19 cell line, and the cell viability during 24 hours incubation was determined by the MTS assay. (C) Concentrations of plasma phospholipids [16] fatty acids in mice. (D) Western blots analysis for expressions of IL-6, TNF-α and myostatin in gastrocnemius muscles of mice (left). Protein levels for ubiquitin ligases, FoxO-1, cathepsin L and calpain in gastrocnemius muscle during cancer and chemotherapy (right). (E) The model illustration for fish oil plus selenium attenuated muscle atrophy after chemotherapy. Under chemotherapy, tumor-bearing mice exhibited a significant increase in the expression of myostatin that activates FoxO-1, and leads to up-regulation of proteasome ubiquitin ligases MuRF-1 and MAFbX. Con, normal control mice; TD, tumor-bearing mice receiving docetaxel; TD-base, tumor-bearing mice receiving docetaxel and background diet; TD-fo+se, tumor bearing mice receiving background diet with additional fish oil and selenium yeast. Data are shown as mean ± SD. n = 5–9 mice/group and each value is an average of three independent experiments. *p < 0.05, **p < 0.01, and ***p < 0.001 denote levels of significant differences between groups.
Mentions: It has been known that myostatin up-regulates the genes involved in the ubiquitin-mediated proteolysis through the NF-κB-independent, FoxO1-dependent mechanism [31]. The FoxO-1 transcription factors can induce skeletal muscle wasting via regulating the atrophy-related genes, namely, the ubiquitin ligase MAFbX and Cathepsin-L [32, 33]. The mRNA and protein levels of FoxO-1 markedly increased in both moderate and severe cachectic mice (Figure 3B). Though FoxO-1 is related to lysosomal atrophy, the mRNA level of cathepsin-L only slightly increased in our experiment (Figure 3B). To confirm that the tumor-induced muscle atrophy truly follows the ubiquitin-proteasome pathway, the expression of ubiquitin ligases was examined by indirect immunofluorescence assay. As shown in Figure 3B and C, the protein levels of MAFbX and MuRF-1 increase in the gastrocnemius muscle of the tumor-bearing mice. Taken together, the tumor-induced muscle atrophy is likely due to elevated levels of TNF-α and myostatin, which act together to activate NF-κB and FoxO1 so as to amplify the expressions of calpain (autolysis) and ubiquitin ligases (ubiquitin-proteasome) (Figure 5E).

Bottom Line: In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation.In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy.The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan.

ABSTRACT
Chemotherapy can cause cachexia, which is manifested by weight loss, inflammation and muscle atrophy. However, the mechanisms of tumor and chemotherapy on skeletal muscle proteolysis, remained unclear. In this report, we demonstrated that tumor-induced myostatin in turn induced TNF-α, thus activating calcium-dependent and proteasomal protein degradation. Chemotherapy activated myostatin-mediated proteolysis and muscle atrophy by elevating IL-6. In tumor-bearing mice under chemotherapy, supplementation with fish oil and selenium prevented a rise in IL-6, TNF-α and myostatin and muscle atrophy. The findings presented here allow us to better understand the molecular basis of cancer cachexia and potentiate nutrition supplementation in future cancer chemotherapy.

No MeSH data available.


Related in: MedlinePlus