Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice
Paolo E. Porporato, … , Stefano Geuna, Andrea Graziani
Paolo E. Porporato, … , Stefano Geuna, Andrea Graziani
Published February 1, 2013; First published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):611-622. https://doi.org/10.1172/JCI39920.
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Categories: Research Article Muscle biology

Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

Abstract

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a–independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a–independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a–mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

Authors

Paolo E. Porporato, Nicoletta Filigheddu, Simone Reano, Michele Ferrara, Elia Angelino, Viola F. Gnocchi, Flavia Prodam, Giulia Ronchi, Sharmila Fagoonee, Michele Fornaro, Federica Chianale, Gianluca Baldanzi, Nicola Surico, Fabiola Sinigaglia, Isabelle Perroteau, Roy G. Smith, Yuxiang Sun, Stefano Geuna, Andrea Graziani

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Figure 5

UnAG pharmacological treatment protects skeletal muscle from fasting- and denervation-induced atrophy in WT mice.

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UnAG pharmacological treatment protects skeletal muscle from fasting- an...
(A–C) Phosphorylation of AktS473, FoxO3aT32, and p38T180/Y182 in gastrocnemii of WT mice treated with 100 μg/kg UnAG or saline. At the indicated time points, gastrocnemii were removed and processed for Western blot analysis. Shown are representative blots and densitometric analysis of 3 independent experiments, normalized to untreated animals (not shown). (D–F) Mean percent weight loss (D), CSA reduction (E), and CSA frequency distribution (F) of gastrocnemii from fed or 48-hour fasted mice treated twice daily with 100 μg/kg UnAG or saline (n = 5 per group). Frequency distribution was measured in 3 mice per group. In D and E, percent reduction shown is between fasted and fed mice. (G–I) Mean percent weight loss (G), CSA reduction (H), and CSA frequency distribution (I) of gastrocnemii from mice treated with 100 μg/kg UnAG or saline twice daily for 7 days after sciatic nerve resection (n = 5 per group). Frequency distribution was measured in 3 mice per group. In G and H, percent reduction shown is between denervated gastrocnemii and gastrocnemii from the unperturbed side. *P < 0.05, **P < 0.01 vs. saline treatment.