Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia

• Published in: Nature medicine Vol. 22; no. 6; pp. 666 - 671
• Main Authors: Fukawa, Tomoya, Yan-Jiang, Benjamin Chua, Min-Wen, Jason Chua, Jun-Hao, Elwin Tan, Huang, Dan, Qian, Chao-Nan, Ong, Pauline, Li, Zhimei, Chen, Shuwen, Mak, Shi Ya, Lim, Wan Jun, Kanayama, Hiro-omi, Mohan, Rosmin Elsa, Wang, Ruiqi Rachel, Lai, Jiunn Herng, Chua, Clarinda, Ong, Hock Soo, Tan, Ker-Kan, Ho, Ying Swan, Tan, Iain Beehuat, Teh, Bin Tean, Shyh-Chang, Ng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 101/58; 14/34; 42/100; 45/61; 631/114/2407; 631/67/70; 692/699/317; Aged; Animals; Atrophy, Muscular; Biomedicine; Blotting, Western; Body weight; Cachexia; Cachexia - etiology; Cachexia - metabolism; Cancer; Cancer Research; Care and treatment; Cell Line; Cell Line, Tumor; Complications and side effects; Cytokines - drug effects; Cytokines - metabolism; Development and progression; Diagnosis; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Epoxy Compounds - pharmacology; Fatty acid metabolism; Fatty acids; Fatty Acids - metabolism; Female; Gene Expression Profiling; Genetic aspects; Health aspects; Humans; Immunohistochemistry; Infectious Diseases; letter; Male; Metabolic Diseases; Metabolomics; Mice; Middle Aged; Molecular Medicine; Morbidity; Mortality; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscles; Muscular atrophy; Muscular Atrophy - metabolism; Muscular system; Neoplasms - complications; Neoplasms - metabolism; Neurosciences; Oxidation; Oxidation-Reduction; Oxidative stress; Oxidative Stress - drug effects; p38 Mitogen-Activated Protein Kinases - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Prognosis; Risk factors; Stem cells; Stem Cells - metabolism; Stress response; Weight; Singapore
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.4093

Cachexia-inducing tumors release complex factors that promote the increased uptake and burning of fats by muscle, resulting in muscle atrophy—a process that can be blocked if fatty acid oxidation is pharmacologically inhibited. 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 1 , 2 , presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer 3 , 4 , 5 . Additionally, although many people with cachexia show hypermetabolism 3 , 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.