Growth hormone secretagogue receptor‐1a mediates ghrelin's effects on attenuating tumour‐induced loss of muscle strength but not muscle mass

Background Ghrelin may ameliorate cancer cachexia (CC) by preventing anorexia, muscle, and fat loss. However, the mechanisms mediating these effects are not fully understood. This study characterizes the pathways involved in muscle mass and strength loss in the Lewis lung carcinoma (LLC)‐induced cachexia model, and the effects of ghrelin in mice with or without its only known receptor: the growth hormone secretagogue receptor‐1a ((GHSR‐1a), Ghsr+/+ and Ghsr−/−). Methods Five to 7‐month‐old male C57BL/6J Ghsr+/+ and Ghsr−/− mice were inoculated with 1 × 106 heat‐killed (HK) or live LLC cells (tumour implantation, TI). When tumours were palpable (7 days after TI), tumour‐bearing mice were injected with vehicle (T + V) or ghrelin twice/day for 14 days (T + G, 0.8 mg/kg), while HK‐treated mice were given vehicle (HK + V). Body weight and grip strength were evaluated before TI and at termination (21 days after TI). Hindlimb muscles were collected for analysis. Results Less pronounced body weight (BW) loss (87.70 ± 0.98% vs. 83.92 ± 1.23%, percentage of baseline BW in tumour‐bearing Ghsr+/+ vs. Ghsr−/−, P = 0.008), and lower upregulation of ubiquitin‐proteasome system (UPS, MuRF1/Trim63, 5.71 ± 1.53‐fold vs. 9.22 ± 1.94‐fold‐change from Ghsr+/+ HK + V in tumour‐bearing Ghsr+/+ vs. Ghsr‐/‐, P = 0.036) and autophagy markers (Becn1, Atg5, Atg7, tumour‐bearing Ghsr+/+