TY - JOUR
T1 - Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice
AU - Porporato, Paolo E.
AU - Filigheddu, Nicoletta
AU - Reano, Simone
AU - Ferrara, Michele
AU - Angelino, Elia
AU - Gnocchi, Viola F.
AU - Prodam, Flavia
AU - Ronchi, Giulia
AU - Fagoonee, Sharmila
AU - Fornaro, Michele
AU - Chianale, Federica
AU - Baldanzi, Gianluca
AU - Surico, Nicola
AU - Sinigaglia, Fabiola
AU - Perroteau, Isabelle
AU - Smith, Roy G.
AU - Sun, Yuxiang
AU - Geuna, Stefano
AU - Graziani, Andrea
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84873367527&partnerID=8YFLogxK
U2 - 10.1172/JCI39920
DO - 10.1172/JCI39920
M3 - Article
SN - 0021-9738
VL - 123
SP - 611
EP - 622
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -