Interaction of simvastatin and aerobic exercise on expression of mitochondrial and cardioprotective proteins in skeletal and cardiac muscle tissue

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Date

2006-05

Authors

Meaney, Mary Patricia

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Abstract

Simvastatin is a cholesterol-lowering drug designed to lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins also inhibit the production of coenzyme Q (CoQ), which shares the same biosynthetic pathway. CoQ is an essential part of the mitochondrial electron transport chain (ETC) and has antioxidant properties. In addition, statins have been shown to effect the expression of antioxidant enzymes and heat shock proteins. Aerobic exercise has also been shown to have an effect on the aforementioned proteins. Statins and aerobicexercise are often co-prescribed by physicians even though the interaction of statins and exercise in heart and skeletal muscle has not been adequately explored. Purpose: To determine the interaction of simvastatin and exercise on CoQ, catalase (CAT), glutathione peroxidase (GPx), Manganese superoxide dismutase (Mn SOD), and heat shock protein 70 (HSP70) in cardiac muscle tissue and the expression of CoQ in the plantaris. Methods: Female 4-mo-old Sprague-Dawley rats were randomly assigned to four treatment groups (N = 15-18/group): sedentary (SED), sedentary treated with simvastatin (SED+SIM), exercise trained (EX), and exercise trained treated with simvastatin (EX+SIM). Rats assigned to simvastatin treated groups received 10 mg simvastatin (Zocor®)/kg body/eight/day for four weeks. Rats assigned to exercise groups were exercised on a treadmill five days/week for four weeks at about 70% VO2max for a duration that was gradually increased to 60 minutes/day. Twenty-four hours after the last session, the animals were euthanized and the heart and both plantaris muscles were removed. Some hearts were perfused for 20 minutes to rinse away blood and others were subjected to an ischemia-reperfusion (I-R) protocol. Left ventricles of IR hearts and the left plantaris were homogenized in ddH2O and lipids were extracted and analyzed for CoQ by high performance liquid chromatography. CAT, GPx, and Mn SOD activity was measured polarographically and HSP70 expression was determined by western blotting of the supernatant of homogenate from the left ventricular tissue of rinsed hearts. Results: A simvastatin main effect was observed on CoQ expression of cardiac and skeletal muscle, and CAT activity of cardiac muscle tissue. Expression of CoQ was decreased while CAT activity was increased following statin treatment. An exercise main effect was observed on CoQ and HSP70 expression of cardiac muscle tissue. Exercise decreased CoQ expression, but increased HSP70 expression in the heart. An interaction effect was observed on both HSP70 expression and Mn SOD activity of cardiac tissue. With respect to HSP70, treatment with simvastatin slightly attenuated an exercise induced increase in HSP70 expression. With respect to Mn SOD, treatment with simvastatin or exercise decreased activity while a combined treatment restored Mn SOD activity to a level similar to that of animals who received no treatment. Conclusion: Treatment with simvastatin or exercise alone results in alterations in the expression of CoQ and HSP70 and activity of CAT, GPx, and Mn SOD. With co-administration, simvastatin and aerobic exercise interact in such a way that maintains one's antioxidant defenses despite impairment the body's ability to synthesize CoQ.

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