Coenzyme Q₁₀reverses mitochondrial dysfunction in atorvastatin-treated mice and increases exercise endurance

Abstract

Statins are cholesterol-lowering drugs widely used in the prevention of cardiovascular diseases; however, they are associated with various types of myopathies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and thus decrease biosynthesis of low-density lipoprotein cholesterol and may also reduce ubiquinones, essential coenzymes of a mitochondrial electron transport chain, which contain isoprenoid residues, synthesized through an HMG-CoA reductase-dependent pathway. Therefore, we hypothesized that statin treatment might influence physical performance through muscular mitochondrial dysfunction due to ubiquinone deficiency. The effect of two statins, atorvastatin and pravastatin, on ubiquinone content, mitochondrial function, and physical performance was examined by using statin-treated mice. Changes in energy metabolism in association with statin treatment were studied by using cultured myocytes. We found that atorvastatin-treated mice developed muscular mitochondrial dysfunction due to ubiquinone deficiency and a decrease in exercise endurance without affecting muscle mass and strength. Meanwhile, pravastatin at ten times higher dose of atorvastatin had no such effects. In cultured myocytes, atorvastatin-related decrease in mitochondrial activity led to a decrease in oxygen utilization and an increase in lactate production. Conversely, coenzyme Q(10) treatment in atorvastatin-treated mice reversed atorvastatin-related mitochondrial dysfunction and a decrease in oxygen utilization, and thus improved exercise endurance. Atorvastatin decreased exercise endurance in mice through mitochondrial dysfunction due to ubiquinone deficiency. Ubiquinone supplementation with coenzyme Q(10) could reverse atorvastatin-related mitochondrial dysfunction and decrease in exercise tolerance.

Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity

“…We already know that CoQ 10 participates in the electron transport chain in mitochondria (27) and that statins can interfere with CoQ 10 , compromising cellular energy production (28). La Guardia et al (29) have demonstrated that simvastatin inhibits mitochondrial respiration, depletes CoQ 10 , and increases hydrogen peroxide production.…”

Cardiorespiratory Fitness and Incidence of Type 2 Diabetes in United States Veterans on Statin Therapy

“…Furthermore, some 20,21 but not all studies [22][23][24] suggest that improvements in cardiorespiratory fitness in response to exercise training may be blunted by statin therapy. Therefore, in the current study we sought to assess the impact of cardiorespiratory fitness on the incidence of type 2 diabetes in dyslipidemic patients treated with statins.…”

“…Peak exercise capacity (Metabolic Equivalents) was estimated by use of standardized equations. 20,21 One…”

The Effects of Statin Medications on Aerobic Exercise Capacity and Training Adaptations

“…The same finding was presented subsequently by the authors when they analyzed statin use in hypertensive patients [42]. However, statins not only induce muscle pain in humans, reducing physical activity participation and consequently affecting exercise performance, but also as growing evidence indicates in both human and animal models, they may directly compromise aerobic exercise capacity and training adaptations [25,43,44]. Along these lines, Kokkinos and Myers [39] delineated in a recent review that exercise intensity shows a strong association with cardiovascular disease risk; therefore, the reduction in the highest tolerable exercise intensity while taking statins should also be a concern for both clinicians and patients.…”