{"doi":"10.1002/jcsm.13211","title":"EXT418, a novel long‐acting ghrelin, mitigates Lewis lung carcinoma induced cachexia in mice","abstract":"BACKGROUND: Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half-life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long-acting, 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)-induced cachexia in mice. METHODS: heat-killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or EXT418 daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK-treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD-treated mice were pair-fed to the T + V 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. RESULTS: In tumour-bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, P = 0.030; and vs. T + 418 EOD, P = 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour-bearing mice was improved by EXT418 daily (P = 0.010) or EOD (P = 0.008) administration compared with vehicle-treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P = 0.015), IIB (P = 0.037) and IIX (P = 0.050) fibre cross-sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P = 0.005). In skeletal muscles, tumour-induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P ≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P = 0.039). In addition, EXT418 treatments ameliorated the tumour-induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il-6 transcript levels in adipose tissue and circulating IL-10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. CONCLUSIONS: EXT418 mitigates LLC-induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.","journal":"Journal of Cachexia Sarcopenia and Muscle","year":2023,"id":340846,"datarank":0.41588830833596724,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.0,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":732107,"name":"Kora Krumm","orcid":null,"position":1,"is_corresponding":false},{"id":363494,"name":"Ian Lee","orcid":"0000-0001-6057-7176","position":2,"is_corresponding":false},{"id":365254,"name":"Bárbara Anderson","orcid":null,"position":3,"is_corresponding":false},{"id":685669,"name":"Anthony Christiani","orcid":null,"position":4,"is_corresponding":false},{"id":1076356,"name":"Lena Strait","orcid":null,"position":5,"is_corresponding":false},{"id":732106,"name":"Beatrice A. Breckheimer","orcid":null,"position":6,"is_corresponding":false},{"id":732109,"name":"Brynn Irwin","orcid":null,"position":7,"is_corresponding":false},{"id":1075894,"name":"Siyi Jiang","orcid":"0000-0002-5481-2771","position":8,"is_corresponding":false},{"id":1076357,"name":"Artur Rybachok","orcid":null,"position":9,"is_corresponding":false},{"id":1075895,"name":"Amanda Chen","orcid":"0000-0001-9600-9357","position":10,"is_corresponding":false},{"id":1075896,"name":"Lucas Caeiro","orcid":"0000-0001-9633-3384","position":11,"is_corresponding":false},{"id":1076358,"name":"Elizabeth Dacek","orcid":null,"position":12,"is_corresponding":false},{"id":972269,"name":"D. B. Hall","orcid":"0000-0002-5085-8334","position":13,"is_corresponding":false},{"id":1076359,"name":"Caroline H. Kostyla","orcid":null,"position":14,"is_corresponding":false},{"id":972633,"name":"Laura M. Hales","orcid":null,"position":15,"is_corresponding":false},{"id":972270,"name":"Tarik M. Soliman","orcid":"0000-0002-3382-4618","position":16,"is_corresponding":false},{"id":363495,"name":"José M. Garcia","orcid":"0000-0002-4245-1753","position":17,"is_corresponding":false},{"id":1075893,"name":"Haiming L Kerr","orcid":"0000-0003-3142-3690","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:58.548803Z","pmid":"36942661","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}