The Effects of IL6 Dosage and Duration on the Regulation of Protein Turnover in C2C12 Myotubes
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abstract
One of hallmarks of cachexia is skeletal muscle wasting caused by an imbalance between the rates of protein synthesis and degradation. Circulating IL6 is chronically elevated in many types of cachexia, and has emerged as a key regulator of muscle mass. The purpose of this study was to investigate the influence of IL6 dosage and duration of exposure on signaling pathways regulating protein turnover in cultured C2C12 myotubes. Differentiated C2C12 myotubes were treated with two doses (20ng/ml and 100ng/ml) of IL6 for 4h, 24h and 48h. Protein samples were analyzed by Western blots. The low dose (20ng/ml) IL6 treatment transiently (4h) increased phosphorylation of ERK1/2 (T202/Y204), mTOR (S2448) and p70S6K (T389), through an Akt independent mechanism. Inhibition of Stat3 signaling by pyrrolidine dithioicarbamate (PDTC) abolished these anabolic effects of IL6. Chronic treatment (24h) of IL6 at this dosage caused reduced activation of p70S6K phosphorylation, and inhibition of mTOR phosphorylation. However, 100ng/ml IL6 showed an inhibitory effect on p70S6K phosphorylation at 4h, 24h and 48h, and 4EBP1 phosphorylation (T37/46) at 48h. Finally, Atrogin1 protein expression was elevated by 100ng/ml IL6 at all three time points. These results demonstrate IL6 dosage and duration of exposure can differentially effect the regulation of protein turnover in C2C12 muscle cells.
