title: Des-acyl ghrelin exhibits pro-anabolic and anti-catabolic effects on C2C12 myotubes exposed to cytokines and reduces burn-induced muscle proteolysis in rats.
abstract: Although ghrelin and GHRP-2 have been shown to inhibit skeletal muscle proteolysis in rats with burn injury, the effects of des-acyl ghrelin (DAG) have not been reported. In this paper, we demonstrate that continuous 24h administration of DAG attenuated burn-induced EDL muscle proteolysis, and normalized elevated TNFα mRNA. Combined treatment of cultured C2C12 myotubes with TNFα and IFN-γ (TNF+IFN) inhibited protein synthesis and increased protein breakdown; DAG abolished both effects. PI3 kinase inhibition by LY294002 and mTOR inhibition by rapamycin blocked the reversal of the anti-anabolic effects of TNF+IFN-treated myotubes by DAG. DAG also reversed or attenuated the TNF+IFN-induced reduction in phosphorylation of Akt, FOXO1, 4E-BP-1, and GSK-3β in myotubes. Furthermore, DAG attenuated the atrophy signal, phospho-NF-κB, and the mRNA expression of MAFbx and MuRF1, upregulated by TNF+IFN in C2C12 myotubes. We conclude that DAG reduces muscle cachexia produced by injury and proinflammatory cytokines, and that DAG or DAG-based compounds may be useful in treating wasting disorders.
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Sheriff
authors.forename: Nijiati
authors.initials: N
authors.lastname: Kadeer
authors.forename: Rashika
authors.initials: R
authors.lastname: Joshi
authors.forename: Lou Ann
authors.initials: LA
authors.lastname: Friend
authors.forename: J Howard
authors.initials: JH
authors.lastname: James
authors.forename: Ambikaipakan
authors.initials: A
authors.lastname: Balasubramaniam
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D002056:Burns / Q000378:metabolism* / Q000473:pathology; D002100:Cachexia / Q000188:drug therapy; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D054439:Ghrelin / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000071161:Forkhead Box Protein O1
chemical_list: D045930:Anabolic Agents; D002352:Carrier Proteins; D002867:Chromones; D051858:Forkhead Transcription Factors; D054439:Ghrelin; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009124:Muscle Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D044843:SKP Cullin F-Box Protein Ligases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; C499526:Eif4ebp1 protein, rat; C422650:ghrelin, des-n-octanoyl; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C486692:Fbxo32 protein, rat; C499086:Trim63 protein, rat; C546845:mTOR protein, rat; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat