Ghrelin具有食欲增强和对肌肉和脂肪的促进效应，在恶病质治疗中具有潜力。然而，其临床应用受到活性（酰化）ghrelin短半衰期的限制（人类约为11分钟）。EXT418是一种新型长效、持续活性的ghrelin类似物，通过共价连接维生素D衍生物创建而成。本研究评估了EXT418在刘易斯肺癌（LLC）诱导的恶病质小鼠中的作用和机制。雄性C57BL/6J小鼠（5-7个月龄）植入1×106热灭活（HK）或活体LLC细胞。当肿瘤可以触及时，投注车（T+V）或每天注射EXT418（T+418 Daily，0.25 mg/kg/day）或隔日注射（T+418 EOD，0.5 mg/kg/EOD）长达14天，而HK处理的小鼠则注射投注车（HK+V）。T+418 Daily或EOD治疗的小鼠的子集被实验匹配喂食到T+V组。实验结束前评估体成分和握合力。术后在骨骼肌中进行分子标记检测。在移植肿瘤的小鼠中，每天或隔日注射EXT418部分预防了体重下降（T+V vs. T+418 Daily，P = 0.030; 和vs. T+418 EOD，P = 0.020）。在整体脂肪和瘦体量中也观察到了类似的效果。与车组相比，肿瘤患者注射EXT418每天或隔日改善了握力（P = 0.010和P = 0.008）。EXT418对体重和握力的作用部分不依赖于摄食。EXT418每天注射还改善了胫前肌的IIA（P = 0.015）、IIB（P = 0.037）和IIX（P = 0.050）纤维横截面积（CSA），而T+418 EOD改善了红色腓肠肌（GAS）中IIB纤维的CSA（P = 0.005）。在骨骼肌中，肿瘤引起的Fbxo32和Trim63肌纤维蛋白分解基因表达水平增加，而EXT418治疗（TA和GAS/PL）可以改善这种现象，这与摄食无关。EXT418治疗降低了GAS/PL中线粒体自噬标志物Bnip3的表达（P ≤ 0.010）。T+418 EOD的类似效应也观察到在p62基因上（GAS/PL; P = 0.039）。此外，EXT418治疗降低了肌肉Il6转录本水平的肿瘤诱导增加（TA和GAS/PL），这与食物摄入无关。对于脂肪组织和循环IL-10中的Il-6转录本水平，嗜酸性粒细胞增多症肿瘤引起的升高在EXT418治疗时没有显著改变。EXT418没有改变肿瘤质量。EXT418通过减轻骨骼肌炎症、蛋白质分解和线粒体自噬来缓解LLC诱导的恶病质，而不影响肿瘤质量，部分独立于食物摄入。© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

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.Male C57BL/6J mice (5- to 7-month-old) were implanted with 1 × 106 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.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.EXT418 mitigates LLC-induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.