1 research outputs found
EXT418, a novel longâacting 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 halfâlife of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel longâacting, 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)âinduced cachexia in mice. Methods Male C57BL/6J mice (5â to 7âmonthâold) were implanted with 1 Ă 106 heatâkilled (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 HKâtreated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EODâtreated mice were pairâfed 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 tumourâbearing 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 tumourâbearing mice was improved by EXT418 daily (P = 0.010) or EOD (P = 0.008) administration compared with vehicleâtreated 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 crossâsectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P = 0.005). In skeletal muscles, tumourâinduced 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 â€Â 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P = 0.039). In addition, EXT418 treatments ameliorated the tumourâinduced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Ilâ6 transcript levels in adipose tissue and circulating ILâ10 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 LLCâinduced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake