Exercise increases SOCS-3 expression in rat skeletal muscle: potential relationship to IL-6 expression

Suppressor of cytokine signalling-3 (SOCS-3) has been implicated in the onset of insulin resistance in non-muscle tissue. Thus, we examined the effects of exercise training on SOCS-3 expression and the potential role of SOCS-3 in muscle. Female Sprague-Dawley rats (5-8 months) were treadmill trained for 12 weeks and the muscles were removed 24 h after the last bout of exercise. Exercise training increased SOCS-3 mRNA expression by 80% and 154% in the plantaris and soleus muscle, respectively. To mimic the effects of increased SOCS-3 expression, SOCS-3 cDNA was cotransfected with a NF-kappa B (NF-kappaB) luciferase construct into cultured C2C12 myotubes. SOCS-3 overexpression increased NF-kappaB transcriptional activity by 27-fold. The proximal region of the IL-6 gene promoter contains a NF-kappaB consensus site, which contributes to increased IL-6 expression in various tissues. SOCS-3 cDNA was cotransfected into cultured C2C12 myotubes with either the IL-6 luciferase construct or a mutated NF-kappaB IL-6 luciferase construct. SOCS-3 overexpression increased IL-6 transcriptional activity by 15-fold, however, when the NF-kappaB site was mutated SOCS-3 failed to increase IL-6 transcriptional activity. We subsequently found that IL-6 mRNA expression was elevated in the plantaris and soleus muscles of the trained animals compared to the sedentary animals. Finally, exercise induced a significant reduction in IkappaBalpha and increased phosphorylation of Ikappakappa suggesting that NF-kappaB activation was elevated after exercise training. These data suggest that training-induced elevations in SOCS-3 expression in skeletal muscle may contribute to the exercise-induced increase in IL-6 expression through alterations in the mechanisms that mediate NF-kappaB activity.