Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia

Abstract

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer1,2, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer3,4,5. Additionally, although many people with cachexia show hypermetabolism3,6, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell–based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid–induced oxidative stress could be targeted to prevent cancer-induced cachexia.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Modeling cancer-induced cachexia with human cancer cells and myotubes.
Figure 2: Cachectic media induce stress-response signatures and fatty acid metabolism as the primary transcriptional effects in human muscle cells.
Figure 3: Cachectic conditioned media induces lipolysis and fatty acid oxidation as the primary metabolic effects in human muscle cells.
Figure 4: Inhibition of fatty acid–induced oxidative stress blocks cachexia.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Tisdale, M.J. Cachexia in cancer patients. Nat. Rev. Cancer 2, 862–871 (2002).

    Article  CAS  Google Scholar 

  2. von Haehling, S. & Anker, S.D. Cachexia as a major underestimated and unmet medical need: facts and numbers. J. Cachexia Sarcopenia Muscle 1, 1–5 (2010).

    Article  Google Scholar 

  3. Fearon, K.C., Glass, D.J. & Guttridge, D.C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).

    Article  CAS  Google Scholar 

  4. Fearon, K., Arends, J. & Baracos, V. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10, 90–99 (2013).

    Article  CAS  Google Scholar 

  5. Cohen, S., Nathan, J.A. & Goldberg, A.L. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat. Rev. Drug Discov. 14, 58–74 (2015).

    Article  CAS  Google Scholar 

  6. Zuijdgeest-van Leeuwen, S.D. et al. Lipolysis and lipid oxidation in weight-losing cancer patients and healthy subjects. Metabolism 49, 931–936 (2000).

    Article  CAS  Google Scholar 

  7. Guttridge, D.C., Mayo, M.W., Madrid, L.V., Wang, C.Y. & Baldwin, A.S. Jr. NF-κB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289, 2363–2366 (2000).

    Article  CAS  Google Scholar 

  8. McFarlane, C. et al. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-κB-independent, FoxO1-dependent mechanism. J. Cell. Physiol. 209, 501–514 (2006).

    Article  CAS  Google Scholar 

  9. Mori, M. et al. Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. Cancer Res. 51, 6656–6659 (1991).

    CAS  PubMed  Google Scholar 

  10. Bouhadir, K.H. et al. Degradation of partially oxidized alginate and its potential application for tissue engineering. Biotechnol. Prog. 17, 945–950 (2001).

    Article  CAS  Google Scholar 

  11. Silva, E.A., Kim, E.S., Kong, H.J. & Mooney, D.J. Material-based deployment enhances efficacy of endothelial progenitor cells. Proc. Natl. Acad. Sci. USA 105, 14347–14352 (2008).

    Article  CAS  Google Scholar 

  12. Bernet, J.D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014).

    Article  CAS  Google Scholar 

  13. Cosgrove, B.D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014).

    Article  CAS  Google Scholar 

  14. Das, S.K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

    Article  CAS  Google Scholar 

  15. Kawakami, M. et al. Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J. Biochem. 101, 331–338 (1987).

    Article  CAS  Google Scholar 

  16. Feingold, K.R., Doerrler, W., Dinarello, C.A., Fiers, W. & Grunfeld, C. Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis. Endocrinology 130, 10–16 (1992).

    Article  CAS  Google Scholar 

  17. Green, A., Dobias, S.B., Walters, D.J. & Brasier, A.R. Tumor necrosis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase. Endocrinology 134, 2581–2588 (1994).

    Article  CAS  Google Scholar 

  18. van Hall, G. et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J. Clin. Endocrinol. Metab. 88, 3005–3010 (2003).

    Article  CAS  Google Scholar 

  19. Argilés, J.M., Busquets, S., Toledo, M. & López-Soriano, F.J. The role of cytokines in cancer cachexia. Curr. Opin. Support. Palliat. Care 3, 263–268 (2009).

    Article  Google Scholar 

  20. Ebadi, M., Baracos, V.E., Bathe, O.F., Robinson, L.E. & Mazurak, V.C. Loss of visceral adipose tissue precedes subcutaneous adipose tissue and associates with n-6 fatty acid content. Clin. Nutr. S0261-5614(16)00071-6 (2016).

  21. Son, Y., Kim, S., Chung, H.T. & Pae, H.O. Reactive oxygen species in the activation of MAP kinases. Methods Enzymol. 528, 27–48 (2013).

    Article  CAS  Google Scholar 

  22. Mastrocola, R. et al. Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress. Free Radic. Biol. Med. 44, 584–593 (2008).

    Article  CAS  Google Scholar 

  23. Waning, D.L. et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat. Med. 21, 1262–1271 (2015).

    Article  CAS  Google Scholar 

  24. Gao, S. & Carson, J.A. Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes. Am. J. Physiol. Cell Physiol. 310, C66–C79 (2016).

    Article  Google Scholar 

  25. Trendelenburg, A.U., Meyer, A., Jacobi, C., Feige, J.N. & Glass, D.J. TAK-1/p38/nNFκB signaling inhibits myoblast differentiation by increasing levels of Activin A. Skelet. Muscle 2, 3 (2012).

    Article  CAS  Google Scholar 

  26. Min-Wen, J.C., Jun-Hao, E.T. & Shyh-Chang, N. Stem cell mitochondria during aging. Semin. Cell Dev. Biol. 52, 110–118 (2016).

    Article  CAS  Google Scholar 

  27. Woods, M.N. et al. Effect of a dietary intervention and n-3 fatty acid supplementation on measures of serum lipid and insulin sensitivity in persons with HIV. Am. J. Clin. Nutr. 90, 1566–1578 (2009).

    Article  CAS  Google Scholar 

  28. Horowitz, J.D., Chirkov, Y.Y., Kennedy, J.A. & Sverdlov, A.L. Modulation of myocardial metabolism: an emerging therapeutic principle. Curr. Opin. Cardiol. 25, 329–334 (2010).

    Article  Google Scholar 

  29. Lopatin, Y.M. et al. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int. J. Cardiol. 203, 909–915 (2016).

    Article  Google Scholar 

  30. Skuk, D. et al. Intramuscular transplantation of human postnatal myoblasts generates functional donor-derived satellite cells. Mol. Ther. 18, 1689–1697 (2010).

    Article  CAS  Google Scholar 

  31. Khaw, S.L., Min-Wen, C., Koh, C.G., Lim, B. & Shyh-Chang, N. Oocyte factors suppress mitochondrial polynucleotide phosphorylase to remodel the metabolome and enhance reprogramming. Cell Rep. 12, 1080–1088 (2015).

    Article  CAS  Google Scholar 

  32. Selvarasu, S. et al. Combined in silico modeling and metabolomics analysis to characterize fed-batch CHO cell culture. Biotechnol. Bioeng. 109, 1415–1429 (2012).

    Article  CAS  Google Scholar 

  33. Tan, A.H.M. et al. Aberrant presentation of self-lipids by autoimmune B cells depletes peripheral iNKT cells. Cell Rep. 9, 24–31 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all our respective lab mates for their helpful discussion, and E. Peh for technical assistance with mass spectrometry. This work was supported by the Agency for Science Technology and Research (ASTAR) Joint Council Office grant 1431AFG128 (N.S.-C.), the Singapore National Medical Research Council grants NMRC/STaR/0024/2014 and NMRC/GMS/CIRG/1332/2012, Duke-NUS Medical School, and National Cancer Centre Singapore (all to B.T.T.), Polaris program grant SPF2012/001 under the ASTAR Strategic Positioning Fund (Y.S.H.) and the Genome Institute of Singapore (I.B.T. and N.S.-C.).

Author information

Authors and Affiliations

Authors

Contributions

T.F., I.B.T., B.T.T. and N.S.-C. designed the study. T.F., B.C.Y.-J., J.C.M.-W., D.H., C.-N.Q., P.O., Z.L. and H.K. performed experiments in vivo. T.F., B.C.Y.-J., J.C.M.-W., E.T.J.-H., D.H. and P.O. performed experiments in vitro. W.J.L., J.H.L., C.C., H.S.O., K.-K.T. and I.B.T. provided the clinical samples. S.C., S.Y.M. and Y.S.H. performed mass-spectrometry experiments. R.E.M. and R.R.W. performed quantitative phase imaging. T.F., I.B.T., B.T.T. and N.S.-C. wrote the manuscript.

Corresponding authors

Correspondence to Iain Beehuat Tan, Bin Tean Teh or Ng Shyh-Chang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–4 (PDF 7313 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fukawa, T., Yan-Jiang, B., Min-Wen, J. et al. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nat Med 22, 666–671 (2016). https://doi.org/10.1038/nm.4093

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4093

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer