title: 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 cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, 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.
authors.affiliation: Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore.|Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.|Department of Urology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukawa
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.
authors.forename: Benjamin Chua
authors.initials: BC
authors.lastname: Yan-Jiang
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.
authors.forename: Jason Chua
authors.initials: JC
authors.lastname: Min-Wen
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.
authors.forename: Elwin Tan
authors.initials: ET
authors.lastname: Jun-Hao
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.affiliation: Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore.|Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.
authors.forename: Pauline
authors.initials: P
authors.lastname: Ong
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Bioprocessing Technology Institute, Agency for Science Technology and Research, Singapore.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Bioprocessing Technology Institute, Agency for Science Technology and Research, Singapore.
authors.forename: Shi Ya
authors.initials: SY
authors.lastname: Mak
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Wan Jun
authors.initials: WJ
authors.lastname: Lim
authors.affiliation: Department of Urology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Hiro-Omi
authors.initials: HO
authors.lastname: Kanayama
authors.affiliation: School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore.
authors.forename: Rosmin Elsa
authors.initials: RE
authors.lastname: Mohan
authors.affiliation: School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore.
authors.forename: Ruiqi Rachel
authors.initials: RR
authors.lastname: Wang
authors.affiliation: Department of Colorectal Surgery, Singapore General Hospital, Singapore.
authors.forename: Jiunn Herng
authors.initials: JH
authors.lastname: Lai
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.|Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Clarinda
authors.initials: C
authors.lastname: Chua
authors.affiliation: Department of Upper Gastrointestinal and Bariatric Surgery, Singapore General Hospital, Singapore.
authors.forename: Hock Soo
authors.initials: HS
authors.lastname: Ong
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Ker-Kan
authors.initials: KK
authors.lastname: Tan
authors.affiliation: Bioprocessing Technology Institute, Agency for Science Technology and Research, Singapore.
authors.forename: Ying Swan
authors.initials: YS
authors.lastname: Ho
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.|Division of Medical Oncology, National Cancer Centre Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore.
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.affiliation: Laboratory of Cancer Therapeutics, Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore.|Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.|Division of Medical Oncology, National Cancer Centre Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore.|SingHealth/Duke-National University of Singapore Precision Medicine Institute, National Heart Centre, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research, Singapore.
authors.forename: Ng
authors.identifier: 0000-0003-3138-9525
authors.initials: N
authors.lastname: Shyh-Chang
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D055432:Metabolomics; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D013234:Stem Cells / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D048051:p38 Mitogen-Activated Protein Kinases; C054207:etomoxir