title: D-TRP(8)-γMSH Prevents the Effects of Endotoxin in Rat Skeletal Muscle Cells through TNFα/NF-KB Signalling Pathway.
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.
authors.affiliation: Department of Physiology, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Gómez-SanMiguel
authors.affiliation: Department of Physiology, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Villanúa
authors.affiliation: Department of Physiology, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Martín
authors.affiliation: Department of Physiology, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: López-Calderón
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D051858:Forkhead Transcription Factors; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D004731:Endotoxins; D051858:Forkhead Transcription Factors; D018972:Insulin-Like Growth Factor Binding Protein 3; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D016328:NF-kappa B; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C534065:gamma-melanocyte-stimulating factor, Trp(8)-; D007334:Insulin-Like Growth Factor I; D009074:Melanocyte-Stimulating Hormones; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018995:Myosin Heavy Chains