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.
Published by Elsevier Ireland Ltd.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Anabolic Agents / pharmacology
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Animals
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Burns / metabolism*
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Burns / pathology
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Cachexia / drug therapy
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Carrier Proteins / metabolism
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Cells, Cultured
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Chromones / pharmacology
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Forkhead Transcription Factors / metabolism
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Ghrelin / pharmacology*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Interferon-gamma / pharmacology
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Intracellular Signaling Peptides and Proteins
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Mice
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Morpholines / pharmacology
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Muscle Fibers, Skeletal / drug effects*
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Muscle Fibers, Skeletal / metabolism*
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Muscle Fibers, Skeletal / pathology
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Muscle Proteins / genetics
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Nerve Tissue Proteins / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein Biosynthesis / drug effects
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / biosynthesis
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Rats
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Rats, Sprague-Dawley
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SKP Cullin F-Box Protein Ligases / genetics
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Tripartite Motif Proteins
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / pharmacology
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Ubiquitin-Protein Ligases / genetics
Substances
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Anabolic Agents
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Carrier Proteins
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Chromones
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Eif4ebp1 protein, rat
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Forkhead Transcription Factors
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Ghrelin
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Intracellular Signaling Peptides and Proteins
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Morpholines
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Muscle Proteins
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NF-kappa B
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Nerve Tissue Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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RNA, Messenger
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Tripartite Motif Proteins
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Tumor Necrosis Factor-alpha
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ghrelin, des-n-octanoyl
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Foxo1 protein, rat
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Interferon-gamma
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Fbxo32 protein, rat
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SKP Cullin F-Box Protein Ligases
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Trim63 protein, rat
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Ubiquitin-Protein Ligases
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mTOR protein, rat
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Glycogen Synthase Kinase 3
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Sirolimus