EXERCISE TRAINING AND LIPOIC ACID UPREGULATE IRS-1 PROTEIN EXPRESSION IN MUSCLE OF OBESE ZUCKER RATS:

The antioxidant R-(+)-alpha-lipoic acid (R-ALA) enhances insulin action on skeletal muscle of the insulin-resistant obese Zucker rat. We have previously shown that chronic R-ALA treatment combined with endurance exercise training (ET) increases glucose transport in insulin-resistant skeletal muscle in an additive fashion. PURPOSE: The purpose of the present study was to investigate possible cellular mechanisms responsible for this interactive effect. Specifically, we evaluated the effects of R-ALA alone or in combination with ET on insulin-stimulated glucose transport, protein expression of specific insulin signaling factors, and triglyceride content in soleus muscles of the obese Zucker rat. METHODS: Animals either remained sedentary, received R-ALA (30 mg/kg body wt/day), performed ET (daily treadmill running for up to 60 min), or underwent both R-ALA treatment and ET for 2 wk, at which time the above variables were assessed. RESULTS: R-ALA or ET individually increased (p < 0.05) insulin-mediated (2 mU/ml) glucose transport (2-deoxyglucose uptake) in soleus muscle by 45% and 68%, respectively, and this value was increased to the greatest extent (124%) in the combined treatment group. The protein expression of insulin receptor substrate-1 (IRS-1) was 44% less in soleus of obese Zucker rats vs. insulin-sensitive lean Zucker rats. IRS-1 protein was significantly increased after R-ALA alone (30%) or ET alone (31%), and a further enhancement (55%) was observed following the combination treatment in the obese animals. The protein level of the p85 regulatory subunit of phosphatidylinositol-3-kinase, however, was not different among groups. Triglyceride content in soleus muscle of obese Zucker rats was 3.3 times higher than that of lean Zucker rats. This parameter was significantly reduced (32%-44%) following individual or combination treatment with R-ALA and ET. CONCLUSION: These results demonstrate that the improvement of insulin action in insulin-resistant skeletal muscle following R-ALA or ET was associated with an increase in IRS-1 protein and a reduction in triglyceride accumulation. In addition, the interactions of R-ALA and ET resulted in an additional upregulation of this important protein in the insulin signaling pathway. Supported by American Heart Association Grant 9951103Z