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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/E241    most recent 00129.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Plaisance, I. Articles by Brink, M. Search for Related Content PubMed PubMed Citation Articles by Plaisance, I. Articles by Brink, M.

TNF- increases protein content in C₂C₁₂ and primary myotubes by enhancing protein translation via the TNF-R1, PI3K, and MEK

Institute of Physiology, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland

Submitted 26 February 2007 ; accepted in final form 29 October 2007

Recent evidence supports that TNF-, long considered a catabolic factor, may also have a physiological function in skeletal muscle. The catabolic view, mainly based on correlative studies in human and in vivo animal models, was challenged by experiments with myoblasts, in which TNF- induced differentiation. The biological effects of TNF- in differentiated muscle, however, remain poorly understood. In the present study, we tested whether TNF- has growth-promoting effects in myotubes, and we characterized the mechanisms leading to these effects. Treatment of C₂C₁₂ myotubes with TNF- for 24 h increased protein synthesis (PS) and enhanced cellular dehydrogenase activity by 22 and 26%, respectively, without changing cell numbers. These effects were confirmed in myotubes differentiated from primary rat myoblasts. TNF- activated two signaling cascades: 1) ERK1/2 and its target eIF4E and 2) Akt and its downstream effectors GSK-3, p70^S6K, and 4E-BP1. TNF--induced phosphorylation of Akt, and ERK1/2 was inhibited by an antibody against TNF- receptor 1 (TNF-R1). PD-98059 pretreatment abolished TNF--induced phosphorylation of ERK1/2 and eIF4E, whereas PS was only partially inhibited. LY-294002 completely abolished TNF--induced stimulation of PS as well as phosphorylation of Akt and its downstream targets GSK-3, p70^S6K, and 4E-BP1. Rapamycin inhibited TNF--induced phosphorylation of the mTOR C1 target p70^S6K without altering TNF--induced PS and 4E-BP1 phosphorylation. In conclusion, our results provide evidence that TNF- enhances PS in myotubes and that this is based on enhanced protein translation mediated by the TNF-R1 and PI3K-Akt and MEK-ERK signaling cascades.

tumor necrosis factor-; tumor necrosis factor- receptor 1; phosphatidylinositol 3-kinase; mitogen-activated protein kinase/extracellular signal-related kinase