Skip to main content
ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #305063

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

Title: Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

Author
item Porporato, Paolo - Universita Del Piemonte Orientale "amedeo Avogadro"
item Filigheddu, Nicoletta - Universita Del Piemonte Orientale "amedeo Avogadro"
item Reano, Simone - Universita Del Piemonte Orientale "amedeo Avogadro"
item Ferrara, Michele - Universita Del Piemonte Orientale "amedeo Avogadro"
item Angelino, Elia - Universita Del Piemonte Orientale "amedeo Avogadro"
item Gnocchi, Viola - Universita Del Piemonte Orientale "amedeo Avogadro"
item Prodam, Flavia - Universita Del Piemonte Orientale "amedeo Avogadro"
item Ronchi, Giulia - University Of Torino
item Fagoonee, Sharmila - University Of Torino
item Fornaro, Michele - University Of Torino
item Chianale, Federica - Universita Del Piemonte Orientale "amedeo Avogadro"
item Baldanzi, Gianluca - Universita Del Piemonte Orientale "amedeo Avogadro"
item Surico, Nicola - Universita Del Piemonte Orientale "amedeo Avogadro"
item Sinigaglia, Fabiola - Universita Del Piemonte Orientale "amedeo Avogadro"
item Perroteau, Isabelle - University Of Torino
item Smith, Roy - Universita Del Piemonte Orientale "amedeo Avogadro"
item Sun, Yuxiang - Children's Nutrition Research Center (CNRC)
item Geuna, Stefano - University Of Torino
item Graziani, Andrea - Universita Del Piemonte Orientale "amedeo Avogadro"

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/1/2012
Publication Date: 2/1/2013
Citation: Porporato, P.E., Filigheddu, N., Reano, S., Ferrara, M., Angelino, E., Gnocchi, V., Prodam, F., Ronchi, G., Fagoonee, S., Fornaro, M., Chianale, F., Baldanzi, G., Surico, N., Sinigaglia, F., Perroteau, I., Smith, R.G., Sun, Y., Geuna, S., Graziani, A. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. Journal of Clinical Investigation. 123(2):611-622.

Interpretive Summary: Loss of skeletal muscle due to aging, disease, or inactivity has serious health consequences for which there are currently no effective and long-lasting therapies. Ghrelin (acylated ghrelin, AG) is a hormone that stimulates release of growth hormone (GH) and promotes fat accumulation, and its functions are mediated by its receptor, GHSR-1a. The ghrelin gene also produces another hormone called unacylated ghrelin (UnAG), which doesn’t activate GHSR-1a and has no effect on GH release. GH is known to have protective effects on muscle, but GH therapy has been associated with increased cancer risk. We have studied the effects of AG and UnAG on muscle loss. Our results demonstrate that both AG and UnAG can effectively prevent muscle loss. Since UnAG has no effect on GH release, it offers a unique property - having great therapeutic potential for prevention and/or treatment of muscle loss, but will not increase the risk of cancer. Further pre-clinical/clinical trials would be beneficial to fully explore the therapeutic potential of AG and UnAG in muscle wasting diseases.

Technical 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 PI3KB-, 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.