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MUSCLE CELL BIOLOGY AND CELL MOTILITY

IFN- does not mimic the catabolic effects of TNF-

Department of Physiology, University of Kentucky, Lexington, Kentucky

Submitted 25 June 2007 ; accepted in final form 4 October 2007

Cachexia is common in chronic inflammatory diseases and is attributed, in part, to an elevation of circulating proinflammatory cytokines. TNF- is the prototype in this category. IFN- is also thought to play a role, but the evidence supporting this model is primarily indirect. To determine the direct effects of IFN- stimulation on muscle cells, we selected key components of the procatabolic signaling pathways by which TNF- stimulates protein loss. We tested two hypotheses: 1) IFN- mimics TNF- signaling by increasing intracellular oxidant activity and activating MAPKs and NF-B and 2) IFN- increases the expression of the ubiquitin ligases atrogin1/MAFbx and muscle-specific ring finger protein 1 (MuRF1). Results showed that treatment with IFN- at 60 ng/ml increased Stat1 phosphorylation after 15 min, indicating receptor activation. IFN- had no effect on cytosolic oxidant activity, as measured by 2',7'-dichlorofluorescein oxidation. Nor did IFN- activate JNK, ERK1/2, or p38 MAPK, as assessed by Western blot. Treatment for up to 60 min did not decrease IB- protein levels, as measured by Western blot analysis, or the DNA binding activity of NF-B, as measured by EMSA. After 6 h, IFN- decreased Akt phosphorylation and increased atrogin1/MAFbx and MuRF1 mRNA. Daily treatment for up to 72 h did not alter adult fast-type myosin heavy chain content or the total protein-to-DNA ratio. These data show that responses of myotubes to IFN- and TNF- differ markedly and provide little evidence for a direct catabolic effect of IFN- on muscle.

skeletal muscle; cachexia; oxidative stress; C2C12; atrophy; tumor necrosis factor-; interferon-