{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:47:29Z","timestamp":1791946049919,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from <jats:italic>Apc<\/jats:italic><jats:sup>Min\/+<\/jats:sup> male mice, a mouse model of intestine and colon cancer, aged of 13 and 23\u00a0weeks, and compared with wild type age\u2010matched C57BL\/6J littermates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010three\u2010week\u2010old <jats:italic>Apc<\/jats:italic> mice recapitulated important features of cancer cachexia including body weight loss (\u221216%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), muscle atrophy (<jats:italic>gastrocnemius<\/jats:italic> muscle: \u221253%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), and weakness (\u221250% in <jats:italic>tibialis anterior<\/jats:italic> muscle force, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), increased expression of atrogens (7\u2010fold increase in MuRF1 transcript level, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and down\u2010regulation of Akt\u2013mTOR pathway (3.3\u2010fold increase in 4EBP1 protein content, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (<jats:italic>Pcx<\/jats:italic>: +90%, <jats:italic>Pck1<\/jats:italic>: +85%), and decreased expression of glycolytic (<jats:italic>Slc2a2<\/jats:italic>: \u221240%, <jats:italic>Gk<\/jats:italic>: \u221230%, <jats:italic>Pklr<\/jats:italic>: \u221260%), ketogenic (<jats:italic>Hmgcs2<\/jats:italic>: \u221255%, <jats:italic>Bdh1<\/jats:italic>: \u221280%), lipolytic\/fatty oxidation (<jats:italic>Lipe<\/jats:italic>: \u221250%, <jats:italic>Mgll<\/jats:italic>: \u221260%, <jats:italic>Cpt2<\/jats:italic>: \u221260%, <jats:italic>Hadh<\/jats:italic>: \u221230%), and lipogenic (<jats:italic>Acly<\/jats:italic>: \u221230%, <jats:italic>Acacb<\/jats:italic>: \u221270%, <jats:italic>Fasn<\/jats:italic>: \u221245%) genes. The hypothalamic pituitary\u2013adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin\u2010releasing hormone in the hypothalamus (2\u2010fold increase, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), adrenocorticotropic hormone receptor (3.4\u2010fold increase, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), and steroid biosynthesis enzymes (<jats:italic>Cyp21a1<\/jats:italic>, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001, and <jats:italic>Cyp11b1<\/jats:italic>, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), skeletal muscle (+17%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), and liver (+24%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) of cachectic 23\u2010week\u2010old <jats:italic>Apc<\/jats:italic> mice. A comparative transcriptional analysis with dexamethasone\u2010treated C57BL\/6J mice indicated that the activation of the hypothalamic\u2013pituitary\u2013adrenal axis in 23\u2010week\u2010old <jats:italic>Apc<\/jats:italic><jats:sup><jats:italic>Min\/+<\/jats:italic><\/jats:sup> mice was significantly associated with the transcription of glucocorticoid\u2010responsive genes in skeletal muscle (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and liver (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). The transcriptional regulation of glucocorticoid\u2010responsive genes was also observed in the <jats:italic>gastrocnemius<\/jats:italic> muscle of Lewis lung carcinoma tumour\u2010bearing mice and in <jats:italic>KPC<\/jats:italic> mice (<jats:italic>tibialis anterior<\/jats:italic> muscle and liver).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings highlight the role of the hypothalamic\u2013pituitary\u2013adrenal\u2010glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12939","type":"journal-article","created":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T07:15:19Z","timestamp":1647069319000},"page":"1686-1703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Hypothalamic\u2013pituitary\u2013adrenal axis activation and glucocorticoid\u2010responsive gene expression in skeletal muscle and liver of <i>Apc<\/i> mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Agn\u00e8s","family":"Martin","sequence":"first","affiliation":[{"name":"Univ Lyon, UJM\u2010Saint\u2010Etienne, Laboratoire Interuniversitaire de Biologie de la Motricit\u00e9, EA7424, F\u201042023  Saint\u2010Etienne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josiane","family":"Castells","sequence":"additional","affiliation":[{"name":"Univ Lyon, UJM\u2010Saint\u2010Etienne, Laboratoire Interuniversitaire de Biologie de la Motricit\u00e9, EA7424, F\u201042023  Saint\u2010Etienne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentine","family":"Allibert","sequence":"additional","affiliation":[{"name":"Univ Lyon, UJM\u2010Saint\u2010Etienne, Laboratoire Interuniversitaire de Biologie de la Motricit\u00e9, EA7424, F\u201042023  Saint\u2010Etienne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9a","family":"Emerit","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoGene (INMG) Univ Lyon, Universit\u00e9 Lyon 1, CNRS UMR 5310, INSERM U 1217  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Zolotoff","sequence":"additional","affiliation":[{"name":"Univ Lyon, UJM\u2010Saint\u2010Etienne, Laboratoire Interuniversitaire de Biologie de la Motricit\u00e9, EA7424, F\u201042023  Saint\u2010Etienne 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Univ Lyon, Universit\u00e9 Claude Bernard Lyon 1, INSERM 1052, CNRS 5286  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Bartholin","sequence":"additional","affiliation":[{"name":"Centre L\u00e9on B\u00e9rard, Centre de recherche en canc\u00e9rologie de Lyon (CRCL) Univ Lyon, Universit\u00e9 Claude Bernard Lyon 1, INSERM 1052, CNRS 5286  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Institut NeuroMyoGene (INMG) Univ Lyon, Universit\u00e9 Lyon 1, CNRS UMR 5310, INSERM U 1217  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010C\u00e9cile","family":"Durieux","sequence":"additional","affiliation":[{"name":"Univ Lyon, UJM\u2010Saint\u2010Etienne, Laboratoire Interuniversitaire de Biologie de la Motricit\u00e9, EA7424, F\u201042023  Saint\u2010Etienne 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