Abstract
HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training.
Highlights
HMG-CoA reductase inhibitors reduce the synthesis of mevalonate, an important intermediary compound necessary for cholesterol production
We found that two weeks of statin treatment significantly impaired muscle function as demonstrated by decreased running wheel activity, grip strength, and maximal isometric force
Exercise training increased mitochondrial content and myofiber CSA while decreasing oxidative stress (4-HNE) in mice receiving saline, yet these beneficial adaptations were compromised concomitant with statin treatment
Summary
HMG-CoA reductase inhibitors (statins) reduce the synthesis of mevalonate, an important intermediary compound necessary for cholesterol production. Exercise Training and Statins pharmacological means of decreasing hypercholesterolemia and reducing cardiovascular disease (CVD) risk. They are considered a safe class of drugs, they carry a significantly elevated risk of skeletal muscle myopathy, ranging from fatigue and weakness to rhabdomyolysis, a potentially fatal condition. Myopathy is estimated to occur in 10% of all statin users [1, 2, 3, 4]. Recent results from the Statins on Skeletal Muscle Function and Performance (STOMP) clinical trial suggest no impact of long-term (6 months) atorvastatin on muscle strength or capacity, yet significant elevation of serum creatine kinase (CK) and myalgia [5, 6]
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