Abstract
Sepsis induces anorexia and muscle wasting secondary to an increase in muscle proteolysis. Melanocyte stimulating hormones (MSH) is a family of peptides that have potent anti-inflammatory effects. Melanocortin receptor-3 (MC3-R) has been reported as the predominant anti-inflammatory receptor for melanocortins. The aim of this work was to analyse whether activation of MC3-R, by administration of its agonist D-Trp(8)-γMSH, is able to modify the response of skeletal muscle to inflammation induced by lipopolysaccharide endotoxin (LPS) or TNFα. Adult male rats were injected with 250 μg/kg LPS and/or 500 μg/kg D-Trp(8)-γMSH 17:00 h and at 8:00 h the following day, and euthanized 4 hours afterwards. D-Trp(8)-γMSH decreased LPS-induced anorexia and prevented the stimulatory effect of LPS on hypothalamic IL-1β, COX-2 and CRH as well as on serum ACTH and corticosterone. Serum IGF-I and its expression in liver and gastrocnemius were decreased in rats injected with LPS, but not in those that also received D-Trp(8)-γMSH. However, D-Trp(8)-γMSH was unable to modify the effect of LPS on IGFBP-3. In the gastrocnemius D-Trp(8)-γMSH blocked LPS-induced decrease in pAkt, pmTOR, MHC I and MCH II, as well as the increase in pNF-κB(p65), FoxO1, FoxO3, LC3b, Bnip-3, Gabarap1, atrogin-1, MuRF1 and in LC3a/b lipidation. In L6 myotube cultures, D-Trp(8)-γMSH was able to prevent TNFα-induced increase of NF-κB(p65) phosphorylation and decrease of Akt phosphorylation as well as of IGF-I and MHC I expression. These data suggest that MC3-R activation prevents the effect of endotoxin on skeletal wasting by modifying inflammation, corticosterone and IGF-I responses and also by directly acting on muscle cells through the TNFα/NF-κB(p65) pathway.
MeSH terms
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Adrenal Glands / drug effects
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Adrenal Glands / pathology
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Animals
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Autophagy / drug effects
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Body Weight / drug effects
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Eating / drug effects
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Endotoxins / toxicity*
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Forkhead Transcription Factors
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Hypothalamus / drug effects
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Hypothalamus / pathology
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Inflammation / pathology
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor I / metabolism
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Lipopolysaccharides / toxicity
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Liver / drug effects
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Liver / pathology
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Male
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Melanocyte-Stimulating Hormones / pharmacology*
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology*
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Myosin Heavy Chains / metabolism
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NF-kappa B / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Rats, Wistar
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Real-Time Polymerase Chain Reaction
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / metabolism
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Tripartite Motif Proteins / genetics
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Tripartite Motif Proteins / metabolism
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Tumor Necrosis Factor-alpha / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Endotoxins
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Forkhead Transcription Factors
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Insulin-Like Growth Factor Binding Protein 3
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Lipopolysaccharides
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Muscle Proteins
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NF-kappa B
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Tripartite Motif Proteins
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Tumor Necrosis Factor-alpha
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gamma-melanocyte-stimulating factor, Trp(8)-
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Insulin-Like Growth Factor I
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Melanocyte-Stimulating Hormones
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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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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Myosin Heavy Chains
Grants and funding
This work was funded by grants to ALC from Ministerio de Economía y Competitividad n° BFU2012-38468 (
http://www.mineco.gob.es/portal/site/mineco/idi) and to ABGS predoctoral grant from Universidad Complutense (
http://www.ucm.es/ucm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.