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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 January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):611-622. https://doi.org/10.1172/JCI39920.
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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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