The role of mitochondria in statin‐induced myopathy

Apostolopoulou, Maria; Corsini, Alberto; Roden, Michael

doi:10.1111/eci.12461

Cited by 123 publications

(106 citation statements)

References 73 publications

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“…A growing body of evidence suggests that the inhibition of cholesterol synthesis itself may not be the primary cause of these deleterious side effects. Instead, the inhibition of protein prenylation (Wang et al 2008;Correale et al 2014) and an impaired mitochondrial homeostasis (Golomb and Evans 2008;Apostolopoulou et al 2015) may be among the underlying mechanisms leading to the side effects of statins. One proposed mechanism suggests that reduced levels of the ubiquinone Coenzyme Q 10 (CoQ 10 ) cause impaired mitochondrial calcium homeostasis in the muscles of statin-treated humans (Galtier et al 2012;Sirvent et al 2012), but this is highly controversial (Apostolopoulou et al 2015;Auer et al 2016).…”

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confidence: 99%

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Oks

Lewin

Goncalves³

et al. 2018

Genetics

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The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway's enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPR, can protect yeast, , and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. Using, we found that the UPR does not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, in the UPR upregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNA interference (RNAi) screen identified two UPR transcription factors, ATFS-1 and DVE-1, as regulators of HMGS-1 A comprehensive analysis of the pathway's enzymes found that, in addition to HMGS-1, the UPR upregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPR 3response. Thus, the UPR acts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPR and consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.

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confidence: 99%

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Oks

Lewin

Goncalves³

et al. 2018

Genetics

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“…Statins, the primary choice of hypercholesterolemia treatment mainly through inhibition of limiting enzyme HMG CoA reductase, reduce the synthesis of hepatic cholesterol to reduce plasma cholesterol levels and is now considered the choice for treatment of atherosclerotic cardiovascular diseases. [23,24] Our finding is a reference report for the detail mechanism study using HFHCD induced hypercholesterolemia mice model. [2,3] The supplementary of CoQ10 could relieve the statins side effects in skeleton muscle and liver and counteract mitochondrial dysfunctions in plantaris muscle and increased exercise endurance.…”

Section: Discussionmentioning

confidence: 68%

Ubiquinone Ameliorates Simvastatin Induced Respiratory Chain Complex Function Impairment in High‐Fat High‐Cholesterol Diet Fed Mice

Wang¹,

Zhang²,

Feng

et al. 2019

Euro J Lipid Sci & Tech

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Long‐term statins therapy is the primary treatment of hyperlipidemia. A ubiquinone (Co‐enzyme Q10, CoQ10) supplement ameliorates the statins side effects, including skeletal muscle and liver damage, whereas the mechanism involving respiratory chain complex function in a hyperlipidemia animal model remains unknown. Herein, it is reported that the administration of CoQ10 increases plasma CoQ10 level significantly without affecting the lipid lowering effects of statins in high‐fat high cholesterol diet fed mice. Compared with thr statins group, the combination therapy of CoQ10 and statin (Simva + CoQ10) reduces the activity enhancement of plasma CK, ALT, and AST, and restores the activity of complex I in skeletal muscle (2.7‐fold increased) and liver (42% increased). Moreover, the activities of complex II are increased in the muscle (29% increased) and liver (5.8‐folds increased) significantly. Statins decrease the total CoQ10 concentration in mitochondria, while Simva + CoQ10 restore the total CoQ10 concentration in mitochondria from muscle (41% increased) and liver (1.1‐folds increased), respectively. Therefore, administration of CoQ10 ameliorates the function loss of mitochondria respiratory chain complex induced by statins in muscle and liver are concluded. Practical Applications: Statins are widely used in clinical treatment of hypercholesterolemia and atherosclerotic diseases via inhibiting the synthesis of mevalonic acid to achieve the purpose of reducing endogenous cholesterol loading, to display anti‐inflammatory effects, and to stabilize the atherosclerotic plaques. However, the shortage of MVA may cause the low level of ubiquinone which subsequently leads to increasing various side effects, including muscle and liver damage. This study introduces a novel combined administration which could ameliorate the statins induced muscle and liver damage for hypercholesterolemia individuals. Moreover, the method shows a beneficial effect on mitochondrion integrity and functions in skeletal muscle and liver. Statin administration inhibits the 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGCoA‐R), which subsequently decreases the level of endogenous Co enzyme Q10 (CoQ). CoQ supplementation increases the level of CoQ in mitochondria, and ameliorates the function loss of mitochondrial respiratory chain complex induced by statins.

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“…It has been suggested that statins, by lowering cholesterol, may affect mouse membrane calveolae, important in fatty acid transport [29]. Statins have been implicated in impairing mitochondrial function, evidenced by increased lactate production, elevated intramuscular lipid stores, decreased mitochondrial activity (measured by a decrease in cytochrome C activity) and lower CoQ10 levels [30,31]. However, despite the above, it has been found that a decrease in circulating CoQ10 does not result in a reduction in muscle CoQ10 [32].…”

Section: Discussionmentioning

confidence: 99%

Statins Do Not Impair Whole-body Fat Oxidation During Moderate-intensity Exercise in Dyslipidemic Adults

Matuszek

Grant

2018

Exerc Med

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The role of mitochondria in statin‐induced myopathy

Abstract: Background Statins inhibit hydroxymethylglutaryl-coenzyme A reductase, decrease plasma low-density lipoprotein cholesterol and reduce cardiovascular morbidity and mortality. They can also exert adverse effects, mostly affecting skeletal muscle, ranging from mild myalgia to rhabdomyolysis.

Cited by 123 publications

References 73 publications

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Ubiquinone Ameliorates Simvastatin Induced Respiratory Chain Complex Function Impairment in High‐Fat High‐Cholesterol Diet Fed Mice

Statins Do Not Impair Whole-body Fat Oxidation During Moderate-intensity Exercise in Dyslipidemic Adults

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