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However, its clinical use is limited by the short half\u2010life of active (acylated) ghrelin (~11\u00a0min in humans). EXT418 is a novel long\u2010acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)\u2010induced cachexia in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male C57BL\/6J mice (5\u2010 to 7\u2010month\u2010old) were implanted with 1\u00a0\u00d7\u00a010<jats:sup>6<\/jats:sup> heat\u2010killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T\u00a0+\u00a0V) or <jats:italic>EXT418<\/jats:italic> daily (T\u00a0+\u00a0418 Daily, 0.25\u00a0mg\/kg\/day) or every other day (T\u00a0+\u00a0418 EOD, 0.5\u00a0mg\/kg\/EOD) for up to 14\u00a0days, whereas HK\u2010treated mice were given vehicle (HK\u00a0+\u00a0V). Subsets of T\u00a0+\u00a0418 Daily or EOD\u2010treated mice were pair\u2010fed to the T\u00a0+\u00a0V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In tumour\u2010bearing mice, administration of <jats:italic>EXT418<\/jats:italic> daily or EOD partially prevented weight loss (T\u00a0+\u00a0V vs. T\u00a0+\u00a0418 Daily, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.030; and vs. T\u00a0+\u00a0418 EOD, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour\u2010bearing mice was improved by <jats:italic>EXT418<\/jats:italic> daily (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.010) or EOD (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.008) administration compared with vehicle\u2010treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. <jats:italic>EXT418<\/jats:italic> daily administration also improved type IIA (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.015), IIB (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.037) and IIX (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.050) fibre cross\u2010sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; <jats:italic>P\u00a0=<\/jats:italic>\u00a00.005). In skeletal muscles, tumour\u2010induced increases in atrogenes <jats:italic>Fbxo32<\/jats:italic> and <jats:italic>Trim63<\/jats:italic> were ameliorated by EXT418 treatments (TA and GAS\/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker <jats:italic>Bnip3<\/jats:italic> (GAS\/PL; <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.010). Similar effects of EXT418 EOD were observed in p62 (GAS\/PL; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.039). In addition, EXT418 treatments ameliorated the tumour\u2010induced elevation in muscle <jats:italic>Il6<\/jats:italic> transcript levels (TA and GAS\/PL), independently of food intake. <jats:italic>Il\u20106<\/jats:italic> transcript levels in adipose tissue and circulating IL\u201010 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>EXT418 mitigates LLC\u2010induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13211","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T09:45:49Z","timestamp":1679391949000},"page":"1337-1348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["EXT418, a novel long\u2010acting ghrelin, mitigates Lewis lung carcinoma induced cachexia in mice"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3142-3690","authenticated-orcid":false,"given":"Haiming L.","family":"Kerr","sequence":"first","affiliation":[{"name":"Geriatric Research, Education and Clinical Center Veterans Affairs Puget Sound 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Chen","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center Veterans Affairs Puget Sound Health Care System  Seattle Washington USA"},{"name":"Department of Medicine, Division of Gerontology and Geriatric Medicine University of Washington School of Medicine  Washington Seattle USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Caeiro","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center Veterans Affairs Puget Sound Health Care System  Seattle Washington USA"},{"name":"Department of Medicine, Division of Gerontology and Geriatric Medicine University of Washington School of Medicine  Washington Seattle USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Dacek","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and 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St. Newton Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4245-1753","authenticated-orcid":false,"given":"Jose M.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Geriatric Research, Education and Clinical Center Veterans Affairs Puget Sound Health Care System  Seattle Washington USA"},{"name":"Department of Medicine, Division of Gerontology and Geriatric Medicine University of Washington School of Medicine  Washington Seattle USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1159\/000346590"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12023"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-828"},{"key":"e_1_2_8_5_1","first-page":"611","article-title":"Acylated and unacylated ghrelin impair 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Cachexia Acutely after Autologous Stem Cell Transplant","author":"Anderson LJ","year":"2019","journal-title":"Cancers 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