title: 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.affiliation: Department of Translational Medicine, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), and Biotechnology Center for Applied Medical Research (BRMA), Università del Piemonte Orientale "Amedeo Avogadro" — Alessandria, Novara, Vercelli, Italy.
authors.forename: Paolo E
authors.initials: PE
authors.lastname: Porporato
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Filigheddu
authors.forename: Simone
authors.initials: S
authors.lastname: Reano
authors.forename: Michele
authors.initials: M
authors.lastname: Ferrara
authors.forename: Elia
authors.initials: E
authors.lastname: Angelino
authors.forename: Viola F
authors.initials: VF
authors.lastname: Gnocchi
authors.forename: Flavia
authors.initials: F
authors.lastname: Prodam
authors.forename: Giulia
authors.initials: G
authors.lastname: Ronchi
authors.forename: Sharmila
authors.initials: S
authors.lastname: Fagoonee
authors.forename: Michele
authors.initials: M
authors.lastname: Fornaro
authors.forename: Federica
authors.initials: F
authors.lastname: Chianale
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
authors.forename: Nicola
authors.initials: N
authors.lastname: Surico
authors.forename: Fabiola
authors.initials: F
authors.lastname: Sinigaglia
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perroteau
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Sun
authors.forename: Stefano
authors.initials: S
authors.lastname: Geuna
authors.forename: Andrea
authors.initials: A
authors.lastname: Graziani
mesh_terms: D000215:Acylation; D000818:Animals; D002100:Cachexia / Q000378:metabolism / Q000517:prevention & control; D002460:Cell Line; D054439:Ghrelin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D054439:Ghrelin; D046912:Multiprotein Complexes; D054440:Receptors, Ghrelin; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases