Proinflammatory cytokine impairment of insulin-like growth factor I-induced protein synthesis in skeletal muscle myoblasts requires ceramide

Endocrinology. 2004 Oct;145(10):4592-602. doi: 10.1210/en.2003-1749. Epub 2004 Jul 15.

Abstract

GH and IGF-I control over 80% of postnatal growth. We recently established that TNFalpha impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasts. Here we extend these results by showing that ceramide, a second messenger in both TNFalpha and IL-1beta receptor signaling pathways, is a key downstream sphingosine-based lipid that leads to IGF-I resistance. A cell-permeable ceramide analog, C2-ceramide, inhibits IGF-I-induced protein synthesis by 65% and blocks the ability of IGF-I to increase expression of two key myogenic factors, myogenin and MyoD. Identical results were obtained with both TNFalpha and IL-1beta (1 ng/ml). Consistent with these data, neutral sphingomyelinase (N-SMase), an enzyme that catalyzes formation of ceramide from sphingomyelin, blocks IGF-I-induced protein synthesis and expression of both myogenin and MyoD. The possibility that cytokine-induced ceramide production is required for disruption of IGF-I biologic activity was confirmed by treating C2C12 myoblasts with inhibitors of all three ceramide-generating pathways. A N-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, D609, reverse the cytokine inhibition of IGF-I-induced protein synthesis by 80% and 45%, respectively. Likewise, an inhibitor of de novo ceramide synthesis, FB1, causes a 50% inhibition. Similarly, all three inhibitors significantly impair the ability of both TNFalpha and IL-1beta to suppress IGF-I-driven expression of myogenin. These experiments establish that ceramide, derived both from sphingomyelin and de novo synthesis, is a key intermediate by which proinflammatory cytokines impair the ability of IGF-I to promote protein synthesis and expression of critical muscle-specific transcription factors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Ceramides / antagonists & inhibitors
  • Ceramides / physiology*
  • Cytokines / physiology*
  • Drug Synergism
  • Humans
  • Inflammation Mediators / physiology*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology*
  • Interleukin-1 / pharmacology
  • Mice
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / biosynthesis*
  • Muscle, Skeletal / metabolism*
  • MyoD Protein / antagonists & inhibitors
  • Myoblasts / metabolism*
  • Myogenin / antagonists & inhibitors
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Recombinant Proteins / pharmacology
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tyrosine / metabolism

Substances

  • Ceramides
  • Cytokines
  • IRS1 protein, human
  • Inflammation Mediators
  • Insulin Receptor Substrate Proteins
  • Interleukin-1
  • Irs1 protein, mouse
  • MYOG protein, human
  • Muscle Proteins
  • MyoD Protein
  • Myog protein, mouse
  • Myogenin
  • Phosphoproteins
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Tyrosine
  • Insulin-Like Growth Factor I
  • Sphingomyelin Phosphodiesterase