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

Klemen Strle, Suzanne R. Broussard, Robert H. McCusker, Wen Hong Shen, Rodney W. Johnson, Gregory G. Freund, Robert Dantzer, Keith W. Kelley

Research output: Contribution to journalArticle

Abstract

GH and IGF-I control over 80% of postnatal growth. We recently established that TNFα impairs the ability of IGF-I to increase protein synthesis and promote expression of myogenin in myoblasis. Here we extend these results by showing that ceramide, a second messenger in both TNFα and IL-1β 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 TNFα and IL-1β (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. AN-SMase inhibitor, glutathione, as well as an acidic sphingomyelinase (A-SMase) inhibitor, B609, 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 TNFα and EL-1β 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.

Original languageEnglish (US)
Pages (from-to)4592-4602
Number of pages11
JournalEndocrinology
Volume145
Issue number10
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Endocrinology

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