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

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.

• Authors: Klemen Strle, Suzanne R Broussard, Robert H McCusker, Wen-Hong Shen, Rodney W Johnson, Gregory G Freund, Robert Dantzer, Keith W Kelley
• Journal: Endocrinology (Endocrinology) Vol. 145 Issue 10 Pg. 4592-602 (Oct 2004) ISSN: 0013-7227 [Print] United States
• PMID: 15256490 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• Animals
• Cell Line
• Ceramides (antagonists & inhibitors, 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, 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)