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