D-TRP(8)-γMSH Prevents the Effects of Endotoxin in Rat Skeletal Muscle Cells through TNFα/NF-KB Signalling Pathway

PLoS One. 2016 May 13;11(5):e0155645. doi: 10.1371/journal.pone.0155645. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / drug effects
  • Adrenal Glands / pathology
  • Animals
  • Autophagy / drug effects
  • Body Weight / drug effects
  • Eating / drug effects
  • Endotoxins / toxicity*
  • Forkhead Transcription Factors
  • Hypothalamus / drug effects
  • Hypothalamus / pathology
  • Inflammation / pathology
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Lipopolysaccharides / toxicity
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Melanocyte-Stimulating Hormones / pharmacology*
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Myosin Heavy Chains / metabolism
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Endotoxins
  • Forkhead Transcription Factors
  • Insulin-Like Growth Factor Binding Protein 3
  • Lipopolysaccharides
  • Muscle Proteins
  • NF-kappa B
  • Tripartite Motif Proteins
  • Tumor Necrosis Factor-alpha
  • gamma-melanocyte-stimulating factor, Trp(8)-
  • Insulin-Like Growth Factor I
  • Melanocyte-Stimulating Hormones
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, rat
  • Ubiquitin-Protein Ligases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Myosin Heavy Chains

Grant support

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.