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Publication
Growth hormone secretagogue receptor-1a mediates ghrelin's effects on
attenuating tumour-induced loss of muscle strength but not muscle mass.
Authors Liu H, Zang P, Lee II, Anderson B, Christiani A, Strait-Bodey L, Breckheimer BA,
Storie M, Tewnion A, Krumm K, Li T, Irwin B, Garcia JM
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Journal of cachexia, sarcopenia and muscle
Year 2021
Date Published 10/1/2021
Volume : Pages 12 : 1280 - 1295
PubMed Reference 34264027
Abstract 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-/- )., 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., 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+/+  < Ghsr-/- , all P < 0.02) were found in
T + V Ghsr+/+ vs. Ghsr-/- mice. Ghrelin attenuated LLC-induced UPS marker
upregulation in both genotypes, [Trim63 was decreased from 5.71 ± 1.53-fold to
1.96 ± 0.47-fold in Ghsr+/+ (T + V vs. T + G: P = 0.032) and 9.22 ± 1.94-fold to
4.72 ± 1.06-fold in Ghsr-/- (T + V vs. T + G: P = 0.008)]. Only in Ghsr+/+ mice
ghrelin ameliorated LLC-induced grip strength loss [improved from 89.24 ± 3.48%
to 97.80 ± 2.31% of baseline (T + V vs. T + G: P = 0.042)], mitophagy markers
[Bnip3 was decreased from 2.28 ± 0.56 to 1.38 ± 0.14-fold (T + V vs. T + G:
P = 0.05)], and impaired mitochondrial respiration [State 3u improved from
698.23 ± 73.96 to 934.37 ± 95.21 pmol/min (T + V vs. T + G: P = 0.05)], whereas
these markers were not improved by ghrelin Ghsr-/- . Compared with Ghsr+/+ ,
Ghsr-/- tumour-bearing mice also showed decreased response to ghrelin in BW
[T + G-treated Ghsr+/+ vs. Ghsr -/- : 91.75 ± 1.05% vs. 86.18 ± 1.13% of
baseline BW, P < 0.001)], gastrocnemius (T + G-treated Ghsr+/+ vs. Ghsr-/- :
96.9 ± 2.08% vs. 88.15 ± 1.78% of Ghsr+/+ HK + V, P < 0.001) and quadriceps
muscle mass (T + G-treated Ghsr+/+ vs. Ghsr-/- : 96.12 ± 2.31% vs. 88.36 ± 1.94%
of Ghsr+/+ HK + V, P = 0.01), and gastrocnemius type IIA (T + G-treated Ghsr+/+
vs. Ghsr-/- : 1250.49 ± 31.72 vs. 1017.62 ± 70.99 µm2 , P = 0.027) and IIB fibre
cross-sectional area (T + G-treated Ghsr+/+ vs. Ghsr-/- : 2496.48 ± 116.88 vs.
2183.04 ± 103.43 µm2 , P = 0.024)., Growth hormone secretagogue receptor-1a
mediates ghrelin's effects on attenuating LLC-induced weakness but not muscle
mass loss by modulating the autophagy-lysosome pathway, mitophagy, and
mitochondrial respiration.




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