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With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer\u2010induced metabolic dysfunction and cachexia. Adenosine monophosphate\u2010activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer\u2010associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer\u2010associated metabolic dysfunction, insulin resistance and cachexia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In vastus lateralis muscle biopsies from <jats:italic>n<\/jats:italic>\u00a0=\u00a026 patients with non\u2010small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant\u2010negative AMPK\u03b12 (kinase\u2010dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: <jats:italic>n<\/jats:italic>\u00a0=\u00a027, WT\u00a0+\u00a0LLC: <jats:italic>n<\/jats:italic>\u00a0=\u00a034, mAMPK\u2010KiDe: <jats:italic>n<\/jats:italic>\u00a0=\u00a023, mAMPK\u2010KiDe\u00a0+\u00a0LLC: <jats:italic>n<\/jats:italic>\u00a0=\u00a038). Moreover, male LLC\u2010tumour\u2010bearing mice were treated with (<jats:italic>n<\/jats:italic>\u00a0=\u00a010)\/without (<jats:italic>n<\/jats:italic>\u00a0=\u00a09) 5\u2010aminoimidazole\u20104\u2010carboxamide ribonucleotide (AICAR) to activate AMPK for 13\u00a0days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue\u2010specific 2\u2010[3H]deoxy\u2010<jats:sc>d<\/jats:sc>\u2010glucose (2\u2010DG) uptake and immunoblotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with NSCLC presented increased muscle protein content of AMPK subunits \u03b11, \u03b12, \u03b22, \u03b31 and \u03b33 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (\u03b11, \u03b12, \u03b22 and \u03b31), fat\u2010free mass (\u03b11, \u03b22 and \u03b31) and fat mass (\u03b11 and \u03b31). Tumour\u2010bearing mAMPK\u2010KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK\u2010KiDe mice displayed lower insulin\u2010stimulated 2\u2010DG uptake in skeletal muscle (quadriceps: \u221235%, soleus: \u221249%, extensor digitorum longus: \u221248%) and the heart (\u221229%) than that in non\u2010tumour\u2010bearing mice. In skeletal muscle, mAMPK\u2010KiDe abrogated the tumour\u2010induced increase in insulin\u2010stimulated TBC1D4<jats:sup>thr642<\/jats:sup> phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour\u2010bearing mice in an AMPK\u2010dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6K<jats:sup>thr389<\/jats:sup> (mTORC1 substrate) and ACC<jats:sup>ser212<\/jats:sup> (AMPK substrate) and rescued cancer\u2010induced insulin intolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK\u2010deficient mice developing metabolic dysfunction in response to cancer, including AMPK\u2010dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer\u2010associated metabolic dysfunction and possibly cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13238","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T05:41:47Z","timestamp":1684302107000},"page":"1631-1647","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Adenosine monophosphate\u2010activated protein kinase is elevated in human cachectic muscle and prevents cancer\u2010induced metabolic dysfunction in mice"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2050-505X","authenticated-orcid":false,"given":"Steffen H.","family":"Raun","sequence":"first","affiliation":[{"name":"Department of Nutrition, Exercise and Sports University of Copenhagen  Copenhagen Denmark"},{"name":"Department of Biomedical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona S.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Exercise and Sports University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Henr\u00edquez\u2010Olgu\u00edn","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Exercise and Sports University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.C. 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