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Idebenone ameliorates statin-induced myotoxicity in atherosclerotic ApoE-/- mice by reducing oxidative stress and
Wenfei Yu1, Wenjing Wu2, Dandan Zhao2
1Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China; University of Health and Rehabilitation Sciences, No. 17, Shandong Road, Shinan district, Qingdao City, Shandong Province, China.
Abstract:
Statins are the first line of choice for the treatment for atherosclerosis, but their use can cause myotoxicity, a common side effect that may require dosage reduction or discontinuation. The exact mechanism of statin-induced myotoxicity is unknown. Previous research has demonstrated that the combination of idebenone and statin yielded superior anti-atherosclerotic outcomes. Here, we investigated the mechanism of statin-induced myotoxicity in atherosclerotic ApoE-/- mice and whether idebenone could counteract it. After administering simvastatin to ApoE-/- mice, we observed a reduction in plaque formation as well as a decrease in their exercise capacity. We observed elevated levels of lactic acid and creatine kinase, along with a reduction in the cross-sectional area of muscle fibers, an increased presence of ragged red fibers, heightened mitochondrial crista lysis, impaired mitochondrial complex activity, and decreased levels of CoQ9 and CoQ10. Two-photon fluorescence imaging revealed elevated H2O2 levels in the quadriceps, indicating increased oxidative stress. Proteomic analysis indicated that simvastatin inhibited the tricarboxylic acid cycle. Idebenone treatment not only further reduced plaque formation but also ameliorated the impaired exercise capacity caused by simvastatin. Our study represents the inaugural comprehensive investigation into the mechanisms underlying statin-induced myotoxicity. We have demonstrated that statins inhibit CoQ synthesis, impair mitochondrial complex functionality, and elevate oxidative stress, ultimately resulting in myotoxic effects. Furthermore, our research marks the pioneering identification of idebenone's capability to mitigate statin-induced myotoxicity by attenuating oxidative stress, thereby safeguarding mitochondrial complex functionality. The synergistic use of idebenone and statin not only enhances the effectiveness against atherosclerosis but also mitigates statin-induced myotoxicity.
Insights
Statins can cause muscle damage by impairing mitochondrial function and increasing oxidative stress. Idebenone counteracts this statin-induced myotoxicity, offering a potential therapeutic strategy for atherosclerosis patients.
Area of Science:
- Biochemistry
- Mitochondrial Biology
- Pharmacology
Background:
- Statins are primary treatments for atherosclerosis but can cause myotoxicity, a side effect with an unknown mechanism.
- Previous studies suggest idebenone combined with statins improves anti-atherosclerotic outcomes.
Purpose of the Study:
- To investigate the mechanism of statin-induced myotoxicity in atherosclerotic mice.
- To determine if idebenone can counteract statin-induced myotoxicity.
Main Methods:
- Administration of simvastatin to ApoE-/- mice.
- Assessment of plaque formation, exercise capacity, muscle fiber characteristics, mitochondrial function, oxidative stress markers (H2O2), and proteomic analysis.
- Evaluation of idebenone's effects on simvastatin-treated mice.
Main Results:
- Simvastatin reduced plaque formation and exercise capacity, elevated lactic acid and creatine kinase, and caused muscle fiber abnormalities and impaired mitochondrial activity.
- Simvastatin increased oxidative stress (H2O2) and inhibited the tricarboxylic acid cycle.
- Idebenone treatment further reduced plaque formation and ameliorated simvastatin-induced exercise capacity impairment.
Conclusions:
- Statins induce myotoxicity by inhibiting Coenzyme Q (CoQ) synthesis, impairing mitochondrial complex function, and increasing oxidative stress.
- Idebenone mitigates statin-induced myotoxicity by reducing oxidative stress and preserving mitochondrial function.
- Combination therapy with idebenone and statins shows promise for enhanced atherosclerosis treatment and reduced myotoxicity.
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