Abstract
Statins are prescribed to treat hypercholesterolemia and to reduce the risk of cardiovascular disease. However, statin users frequently report myalgia, which can discourage physical activity or cause patients to discontinue statin use, negating the potential benefit of the treatment. Although a proposed mechanism responsible for Statin-Associated Myopathy (SAM) suggests a correlation with impairment of mitochondrial function, the relationship is still poorly understood. Here, we provide evidence that long-term treatment of hypercholesterolemic patients with Simvastatin at a therapeutic dose significantly display increased mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), and platelets compared to untreated controls. Furthermore, the amount of superoxide is higher in mitochondria in PBMCs, and platelets from Simvastatin-treated patients than in untreated controls, and the abundance of mitochondrial superoxide, but not mitochondrial respiration trends with patient-reported myalgia. Ubiquinone (also known as coenzyme Q10) has been suggested as a potential treatment for SAM; however, an 8-week course of oral ubiquinone had no impact on mitochondrial functions or the abundance of superoxide in mitochondria from PBMCs, and platelets. These results demonstrate that long-term treatment with Simvastatin increases respiration and the production of superoxide in mitochondria of PBMCs and platelets.
Highlights
Biosynthesis of mevalonate, farnesyl pyrophosphate, and ubiquinone (UQ)
One hypothesis suggests that lower levels of UQ found in plasma, peripheral blood mononuclear cells (PBMCs), and skeletal muscle of statin users result in an impairment of the electron transport chain (ETC), thereby reducing the rate of mitochondrial respiration[17,25,26,27]
We argue that the hypothesis of a negative relationship between statin usage, and mitochondrial function is based on suboptimal experimental setups, and we demonstrate that shortterm Simvastatin therapy at a dose vastly exceeding the pharmacologically relevant dose does impair mitochondrial respiration in human hepatocarcinoma cells cultured in vitro
Summary
Biosynthesis of mevalonate, farnesyl pyrophosphate, and ubiquinone (UQ). UQ, known as coenzyme Q10, mediates the transport of electrons from complex I, and II to complex III in the electron transport chain (ETC)[24]. Mitochondrial parameters were measured in PBMCs, and platelets from the cohort of Simvastatin users and controls. Reserve respiratory capacity was 1.37 fold higher in platelets, and 1.43 fold higher in PBMCs, respectively (P = 0.0038 and P = 0.0027) (Fig. 2C,I) in Simvastatin users than in controls.
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