New insights into mechanisms of statin-associated myotoxicity

doi:10.1016/j.coph.2007.12.010

Current Opinion in Pharmacology

Volume 8, Issue 3, June 2008, Pages 333-338

https://doi.org/10.1016/j.coph.2007.12.010 Get rights and content

Statin drugs represent a major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides the tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, fatigability) occur frequently. Many hypotheses were proposed to explain statin myotoxicity. The goal of this review is to highlight some of the most recent findings that can account for interpreting the pathophysiological mechanisms for statin-induced myotoxicity. Statin-induced myotoxicity appears multifactorial. Apart from the deleterious effect due to a reduction in cholesterol biosynthesis, statins have a direct effect on the respiratory chain of the mitochondria. It is proposed that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling without excluding a direct effect of statin on the sarcoplasmic reticulum. Both mitochondrial and calcium impairments may account for apoptosis process, oxidative stress, and muscle remodeling and degeneration that have been extensively reported to explain statin myotoxicity and functional symptoms described by treated patients.

Introduction

Statin drugs represent the main therapeutic class of lipid lowering molecules that lower total and low-density lipoprotein (LDL) cholesterol. Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Figure 1). Their development over the past 20 years has represented a major medical advance [1]. The benefits of statin treatments in primary and secondary prevention are particularly well documented, and new beneficial aspects are regularly reported. In addition to the benefits of cholesterol lowering, it has been shown that statins present cholesterol-independent effects allowing for improved endothelial function, enhanced stability of atherosclerotic plaques, decreased inflammation and oxidative stress, and inhibited thrombogenic response in the vascular wall [1]. Clinical trials have demonstrated a reduction in cardiovascular-related morbidity and mortality in treated patients with or without coronary artery disease [1]. This therapeutic is the world's fastest growing class of drugs.

The currently used statins are generally well tolerated and present a good safety profile [2]. Nevertheless, adverse effects of statins have been reported such as hepato-toxicity characterized by an increased level of transaminase occurring with an incidence of 0.1–1.9% [3]. A low risk of neuropathy and other minor adverse effects such as generalized gastrointestinal discomfort are also known. The main reported adverse effects of statins are various forms of myotoxicity ranging from myalgias to rhabdomyolysis. These deleterious muscle manifestations occur in 1–7% of statin-treated patients. They do not correlate with the degree of cholesterol lowering effect of the drug used [4, 5].

Many hypotheses have been proposed to explain statin myotoxicity. This review highlights the most recent findings that can account for interpreting the pathophysiological mechanisms for statin-induced myotoxicity.

Section snippets

Clinical and pharmacological aspects

Variable incidence in the myotoxic effect of statins is reported in the literature. This could be partly due to the definition of muscle toxicity. Most clinical trials have defined the toxicity as myalgia or muscle weakness with a level of creatine kinase (CK) greater than 10 times the normal upper limit. However, this biological index is not always associated with clinical symptoms [6, 7]. The clinical symptoms are also difficult to evaluate and somehow subjective from one patient to the

Pathophysiological mechanisms

Various hypotheses have thus been proposed to explain statin-induced muscle injury. It is first important to note that this myotoxicity of statin is dose dependent [17]. Statin effect can be due to an indirect effect through the reduction of cholesterol synthesis or a direct effect on different muscle targets.

Conclusion

At first glance, statin-induced myotoxicity appears multifactorial. Nevertheless, the latest studies performed to elucidate pathophysiological mechanisms of statins on muscle function have assembled some pieces of the puzzle. Besides deleterious effect due to a reduction in cholesterol biosynthesis, statins seem to have a direct effect on the respiratory chain of the mitochondria. This effect depends nevertheless on the type of statin, as discussed earlier. Without excluding a direct effect of

References and recommended readings

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

Acknowledgements

AL is a CNRS senior scientist supported by INSERM and the ‘Leducq Fondation’.

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A novel machine learning-based screening identifies statins as inhibitors of the calcium pump SERCA
2023, Journal of Biological Chemistry
We report a novel small-molecule screening approach that combines data augmentation and machine learning to identify Food and Drug Administration (FDA)-approved drugs interacting with the calcium pump (Sarcoplasmic reticulum Ca²⁺-ATPase, SERCA) from skeletal (SERCA1a) and cardiac (SERCA2a) muscle. This approach uses information about small-molecule effectors to map and probe the chemical space of pharmacological targets, thus allowing to screen with high precision large databases of small molecules, including approved and investigational drugs. We chose SERCA because it plays a major role in the excitation-contraction-relaxation cycle in muscle and it represents a major target in both skeletal and cardiac muscle. The machine learning model predicted that SERCA1a and SERCA2a are pharmacological targets for seven statins, a group of FDA-approved 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors used in the clinic as lipid-lowering medications. We validated the machine learning predictions by using in vitro ATPase assays to show that several FDA-approved statins are partial inhibitors of SERCA1a and SERCA2a. Complementary atomistic simulations predict that these drugs bind to two different allosteric sites of the pump. Our findings suggest that SERCA-mediated Ca²⁺ transport may be targeted by some statins (e.g., atorvastatin), thus providing a molecular pathway to explain statin-associated toxicity reported in the literature. These studies show the applicability of data augmentation and machine learning-based screening as a general platform for the identification of off-target interactions and the applicability of this approach extends to drug discovery.
Coenzyme Q nanodisks counteract the effect of statins on C2C12 myotubes
2021, Nanomedicine: Nanotechnology, Biology, and Medicine
Depletion of coenzyme Q (CoQ) is associated with disease, ranging from myopathy to heart failure. To induce a CoQ deficit, C2C12 myotubes were incubated with high dose simvastatin. This resulted in a concentration-dependent inhibition of cell viability. Simvastatin-induced effects were prevented by co-incubation with mevalonic acid. When myotubes were incubated with 60 μM simvastatin, mitochondrial CoQ content decreased while co-incubation with CoQ nanodisks (ND) increased mitochondrial CoQ levels and improved cell viability. Incubation of myotubes with simvastatin also led to a reduction in oxygen consumption rate (OCR). When myotubes were co-incubated with simvastatin and CoQ ND, the decline in OCR was ameliorated. The data indicate that CoQ ND represent a water soluble vehicle capable of delivering CoQ to cultured myotubes. Thus, these biocompatible nanoparticles have the potential to bypass poor CoQ oral bioavailability as a treatment option for individuals with severe CoQ deficiency syndromes and/or aging-related CoQ depletion.
Muscular complications of statins
2021, Medecine des Maladies Metaboliques
Les statines sont à l’origine de complications musculaires, essentiellement de myalgies, dont la fréquence exacte est difficile à préciser. Ces complications musculaires représentent un véritable défi clinique dans la mesure où l’imputabilité des statines devant des myalgies n’est pas toujours évidente. Certaines circonstances apparaissent favoriser la survenue de complications musculaires sous statines : activité physique ou sportive inhabituelle, insuffisance rénale ou hépatique, hypothyroïdie, myopathie sous-jacente, ainsi que certaines prises médicamenteuses concomitantes. Les myalgies apparaissent plus fréquentes avec l’utilisation de doses élevées et de statines lipophiles. Plusieurs mécanismes sont invoqués dans la survenue des complications musculaires sous statines : diminution de l’ubiquinone et des dérivés isoprénoïdes, modification de l’équilibre calcique dans la cellule musculaire. En pratique clinique, il sera nécessaire de réaliser un dosage de créatine phosphokinase (CPK) en cas de myalgies, ainsi qu’un dépistage d’une éventuelle hypothyroïdie et d’un déficit en vitamine D. En cas de persistance des douleurs musculaires après arrêt des statines, il sera indispensable de réaliser des explorations à la recherche d’une pathologie musculaire sous-jacente. En cas de résolution des myalgies après arrêt des statines, il est conseillé de réintroduire les statines à plus faibles doses et/ou en changeant de molécule, voire en administrant le traitement en prises espacées. Ce n’est qu’en cas d’échec, après plusieurs tentatives de réintroduction d’un traitement par statine, que l’on pourra parler d’intolérance aux statines et envisager, dans ce cas, l’utilisation d’autres agents hypocholestérolémiants.
Statins may be responsible for muscular side effects, mostly myalgia, but their actual frequency is not clear. Statin-associated adverse muscular effects are a clinical challenge because the responsibility of statin treatment in the muscular pain is not obvious in all patients. Unusual physical activity, renal or hepatic failure, hypothyroidism, metabolic or inherited myopathies, and some concomitant medications, are risk factors for statin-associated myalgia. Muscular side effects are more often observed with higher statin doses or with the use of lipophilic statins. Although the precise mechanisms responsible for the statin-associated muscular effects remain elusive, it is suggested that reduction of ubiquinone and isoprenoids and modification of calcium homeostasis within the muscular cell could be involved. When a statin-treated patient complains of myalgia, plasma creatine phosphokinase must be measured as well as tests to detect hypothyroidism and vitamin D deficiency. When symptoms persist after discontinuation of statin treatment, the possibility of neuromuscular or rheumatologic diseases should be explored. When muscular symptoms resolve after statin discontinuation, it is advised to reintroduce statin at a lower dose, or change to another statin molecule and, if needed, prescribe statin less frequently (once or twice a week). It is only after failure of several statin strategies, that the patient will be considered as statin intolerant. In that situation, other hypocholesterolemic treatments should be considered.
C2C12 myoblasts are more sensitive to the toxic effects of simvastatin than myotubes and show impaired proliferation and myotube formation
2021, Biochemical Pharmacology
Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We compared the toxicity of simvastatin of C2C12 myoblasts and myotubes. Since myoblasts can proliferate and fuse to myotubes, myoblasts can be considered as satellite cells and myotubes as mature muscle fibers. Simvastatin increased plasma membrane permeability and decreased the cellular ATP content in both myoblasts and myotubes, but with a stronger effect on myoblasts. While insulin prevented cytotoxicity up to 8 h after addition of simvastatin to myotubes, prevention in myoblasts required simultaneous addition. Mevalonate and geranylgeraniol prevented simvastatin-associated cytotoxicity in both myoblasts and myotubes. Simvastatin impaired the phosphorylation of the insulin receptor (IR β), Akt ser473 and S6rp, and increased phosphorylation of AMPK thr172 in both myotubes and myoblasts, which was prevented by insulin and mevalonate. Simvastatin impaired oxygen consumption and increased superoxide production by myoblasts and myotubes and induced apoptosis via cytochrome c release. In addition, simvastatin impaired proliferation and fusion of myoblasts to myotubes by inhibiting the expression of the nuclear transcription factor MyoD and of the metalloprotease ADAM-12. Decreased expression of the proliferation factor Ki-67 and of ADAM-12 were also observed in gastrocnemius of mice treated with simvastatin. In conclusion, myoblasts were more susceptible to the toxic effects of simvastatin and simvastatin impaired myoblast proliferation and myotube formation. Impaired muscle regeneration may represent a new mechanism of statin myotoxicity.
Mechanisms of statin-associated skeletal muscle-associated symptoms
2020, Pharmacological Research
Citation Excerpt :
Mitochondrial dysfunction is defined as a decrease in the ability of the mitochondria to synthesize high energy compounds such as adenosine 5′ triphosphate (ATP), which may be a consequence of impaired electron transfer across the electron transport chain or of dissipation of the proton gradient across the inner mitochondrial membrane [66]. Many studies have shown that mitochondrial dysfunction may play an important role in the myotoxicity of statins [67–75]. Since the subject has recently been covered by an excellent review [76], we provide only a short overview.
Statins lower the serum low-density lipoprotein cholesterol and prevent cardiovascular events by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase. Although the safety of statins is documented, many patients ingesting statins may suffer from skeletal muscle-associated symptoms (SAMS). Importantly, SAMS are a common reason for stopping the treatment with statins. Statin-associated muscular symptoms include fatigue, weakness and pain, possibly accompanied by elevated serum creatine kinase activity. The most severe muscular adverse reaction is the potentially fatal rhabdomyolysis. The frequency of SAMS is variable but in up to 30% of the patients ingesting statins, depending on the population treated and the statin used. The mechanisms leading to SAMS are currently not completely clarified. Over the last 15 years, several research articles focused on statin-induced mitochondrial dysfunction as a reason for SAMS. Statins can impair the function of the mitochondrial respiratory chain, thereby reducing ATP and increasing ROS production. This can induce mitochondrial membrane permeability transition, release of cytochrome c into the cytosol and induce apoptosis. In parallel, statins inhibit activation of Akt, mainly due to reduced function of mTORC2, which may be related to mitochondrial dysfunction. Mitochondrial dysfunction by statins is also responsible for activation of AMPK, which is associated with impaired activation of mTORC1. Reduced activation of mTORC1 leads to increased skeletal muscle protein degradation, impaired protein synthesis and stimulation of apoptosis. In this paper, we discuss some of the different hypotheses how statins affect skeletal muscle in more detail, focusing particularly on those related to mitochondrial dysfunction and the impairment of the Akt/mTOR pathway.
The effects of statins with a high hepatoselectivity rank on the extra-hepatic tissues; New functions for statins
2020, Pharmacological Research
Statins, as the most common treatment for hyperlipidemia, exert effects beyond their lipid-lowering role which are known as pleiotropic effects. These effects are mainly due to the inhibition of isoprenoids synthesis and consequently blocking prenylation of proteins involved in the cellular signaling pathways regulating cell development, growth, and apoptosis.
Statins target cholesterol synthesis in the liver as the major source of cholesterol in the body and so reduce whole-body cholesterol. The reduced level of cholesterol forces other organs to an adaptive homeostatic reaction to increase their cholesterol synthesis capacity, however, this only occurs when statins have unremarkable access to the extra-hepatic tissues.
In order to reduce the adverse effects of statin on the skeletal muscle, most recent efforts have been towards formulating new statins with the highest level of hepatoselectivity rank and the least level of access to the extra-hepatic tissues; however, the inaccessibility of statins for the extra-hepatic tissues may induce several biological reactions. In this review, we aim to evaluate the effects of statins on the extra-hepatic tissues when statins have unremarkable access to these tissues.

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New insights into mechanisms of statin-associated myotoxicity

Introduction

Section snippets

Clinical and pharmacological aspects

Pathophysiological mechanisms

Conclusion

References and recommended readings

Acknowledgements

Clin Liver Dis

Toxicol Lett

Am J Cardiol

Biochem Pharmacol

Eur J Pharmacol

J Am Coll Cardiol

Biochem Biophys Res Commun

Toxicology

J Pharmacol Sci

J Pharmacol Exp Ther

Toxicol Appl Pharmacol

FASEB J

Atherosclerosis

Statins: a new insight into their mechanisms of action and consequent pleiotropic effects

Pharmacol Rep

Statin safety: an overview and assessment of the data—2005

Am J Cardiol

Mutation rate variation in multicellular eukaryotes: causes and consequences

Nat Rev Genet

Statin myopathy: an update

Curr Opin Rheumatol

Statin-associated myopathy with normal creatine kinase levels

Ann Intern Med

Oxidation injury in patients receiving HMG-CoA reductase inhibitors: occurrence in patients without enzyme elevation or myopathy

Drug Saf

The myotoxicity of statins

Curr Opin Lipidol