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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/C706    most recent 00626.2008v1 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 Google Scholar Articles by Li, W. Articles by Reid, M. B. PubMed PubMed Citation Articles by Li, W. Articles by Reid, M. B.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

Interleukin-1 stimulates catabolism in C2C12 myotubes

Department of Physiology, University of Kentucky, Lexington, Kentucky

Submitted 8 December 2008 ; accepted in final form 20 July 2009

Interleukin-1 (IL-1) is an inflammatory cytokine that has been linked to muscle catabolism, a process regulated by muscle-specific E3 proteins of the ubiquitin-proteasome pathway. To address cellular mechanism, we tested the hypothesis that IL-1 induces myofibrillar protein loss by acting directly on muscle to increase expression of two critical E3 proteins, atrogin1/muscle atrophy F-box (MAFbx) and muscle RING-finger 1 (MuRF1). Experiments were conducted using mature C2C12 myotubes to eliminate systemic cytokine effects and avoid paracrine signaling by nonmuscle cell types. Time-course protocols were used to define the sequence of cellular responses. We found that atrogin1/MAFbx mRNA and MuRF1 mRNA are elevated 60–120 min after myotube exposure to either IL-1 or IL-1β. These responses are preceded by signaling events that promote E3 expression. Both IL-1 isoforms stimulate phosphorylation of p38 mitogen-activated protein kinase and stimulate nuclear factor-B (NF-B) signaling; I-B levels fall and NF-B DNA binding activity increases. Other regulators of E3 expression are unaffected by IL-1 [cytosolic oxidant activity, Forkhead-O (Foxo) activity] or respond paradoxically (AKT). Chronic exposure of C2C12 myotubes over 48 h resulted in reduced myotube width and loss of sarcomeric actin. We conclude that IL-1 and IL-1β act via an oxidant- and AKT/Foxo-independent mechanism to activate p38 MAPK, stimulate NF-B signaling, increase expression of atrogin1/MAFbx and MuRF1, and reduce myofibrillar protein in differentiated myotubes.

skeletal muscle; atrophy; cachexia; cytokines; inflammation