Proinflammatory Cytokine Impairment of Insulin-Like Growth Factor I-Induced Protein Synthesis in Skeletal Muscle Myoblasts Requires Ceramide (original) (raw)

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1Laboratory of Immunophysiology (K.S., S.R.B., R.H.M., W.-H.S., K.W.K.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

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1Laboratory of Immunophysiology (K.S., S.R.B., R.H.M., W.-H.S., K.W.K.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

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1Laboratory of Immunophysiology (K.S., S.R.B., R.H.M., W.-H.S., K.W.K.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

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1Laboratory of Immunophysiology (K.S., S.R.B., R.H.M., W.-H.S., K.W.K.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

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2Integrative Biology (R.W.J.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

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3Department of Pathology (G.G.F.), College of Medicine, University of Illinois, Urbana, Illinois 61801

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4Neurobiologie Intégrative (R.D.), Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Université de Bordeaux 2, Centre National de la Recherche Scientifique, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France

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1Laboratory of Immunophysiology (K.S., S.R.B., R.H.M., W.-H.S., K.W.K.), Department of Animal Sciences, College of Medicine, University of Illinois, Urbana, Illinois 61801

*Address all correspondence and requests for reprints to: Keith W. Kelley, University of Illinois, Laboratory of Immunophysiology, Department of Animal Sciences, 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, Illinois 61801.

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Received:

24 December 2003

Published:

01 October 2004

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Klemen Strle, Suzanne R. Broussard, Robert H. McCusker, Wen-Hong Shen, Rodney W. Johnson, Gregory G. Freund, Robert Dantzer, Keith W. Kelley, Proinflammatory Cytokine Impairment of Insulin-Like Growth Factor I-Induced Protein Synthesis in Skeletal Muscle Myoblasts Requires Ceramide, Endocrinology, Volume 145, Issue 10, 1 October 2004, Pages 4592–4602, https://doi.org/10.1210/en.2003-1749
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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 myoblasts. 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 cellpermeable 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. 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 TNFα and IL-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.

Copyright © 2004 by The Endocrine Society

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