Pharmacology & Therapeutics 175 (2017) 1–16

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Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: S.J. Enna

Myotoxicity of statins: Mechanism of action Patrick du Souich a,b,⁎, Ghislaine Roederer b, Robert Dufour c,d a

Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada c Clinique de Prévention Cardiovasculaire, Institut de Recherche Clinique de Montréal, Canada d Département de nutrition, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada b

a r t i c l e

i n f o

Available online 14 February 2017 Keywords: Statins myopathy Mechanism of action Mitochondria Lactate Chloride channels Muscle remodeling

a b s t r a c t Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D3. © 2017 Elsevier Inc. All rights reserved.

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacokinetic conditions resulting in statin accumulation in the myocyte . 3. Muscular mechanisms underlying the presentation of SIM . . . . . . . . . 4. Prevention/treatment of SIM . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AKT, protein kinase B; AMPK, AMP-activated protein kinase; Bax, Bcl-2-associated X; Bcl-2, B-cell lymphoma 2; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CaMKII, calmodulin kinase II; CaMKK, Ca2+/calmodulin-dependent kinase kinase; CAT, catalase; CK, creatine kinase; ClC-1, chloride channel; CREB, response elementbinding protein; DCA, dichloroacetate; FoxO3, forkhead box O3; FPP, farnesyl pyrophosphate; gCl, resting chloride channel conductance; GGPP, geranylgeranyl pyrophosphate; GLUT4, glucose transporter 4; GPx, glutathione peroxidase; H2O2, hydrogen peroxide; HMG-CoAR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; IGF-1, insulin-like growth factor-1; Insig, insulin-induced gene; LDL-C, low density lipoprotein-cholesterol; LKB1, liver kinase B1; MAFbx or atrogin-1, muscle atrophy F-box; MCT, monocarboxylate transporter; MDR1 or P-glycoprotein, multidrug resistance 1; MEF2, myosin enhance factor 2; mPTP, mitochondrial permeability transition pore; MRP2, multidrug resistance protein 2; mTOR, mammalian target of rapamycin; MuRF-1, muscle RING-finger protein-1; NADH, reduced β-nicotinamide adenine dinucleotide; NTCP, sodium-dependent taurocholate cotransporting polypeptide; O•− 2 , superoxide; OATP, organic anion transporting polypeptide; OR, odds ratio; p38MAPK, p38 mitogen-activated protein kinase; PCSK9, proprotein convertase subtilisin–kexin type 9; PDC, pyruvate dehydrogenase complex; PDK, piruvate dehydrogenase kinases; PGC, transcription factors peroxisome-proliferator-activated receptor coactivator; PPARγ, peroxisome-proliferator activating receptor γ; RhoA, Ras homolog gene family member A; ROS, reactive oxygen species; RYR3, ryanodine receptor 3; SERCA3, sarco-endoplasmic reticulum transporting Ca2+ ATPase 3; SIM, statin-induced myotoxicity; SIRT5, sirtuin 5; SLC, solute carrier transporters; SNP, single nucleotide polymorphism; SOD, superoxide dismutase; SR, sarcoplasmic reticulum; TCA, tricarboxylic acid. ⁎ Corresponding author at: Département de Pharmacologie, Local S-412, Pavillon Roger Gaudry, Université de Montréal, 2900, boul. Édouard-Montpetit, Montréal, Québec H3T 1J4, Canada. E-mail address: [email protected] (P. du Souich).

http://dx.doi.org/10.1016/j.pharmthera.2017.02.029 0163-7258/© 2017 Elsevier Inc. All rights reserved.

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1. Introduction The most effective oral agents for the prevention and treatment of cardiovascular diseases associated to dyslipidemia are the statins. Lovastatin and simvastatin are administered in the inactive lactone form, and pravastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin in the active β-hydroxy acid form. Statins are reversible competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), and as such reduce intracellular synthesis of cholesterol. The pharmacological response of statins depends upon their ability to reach the hepatocyte where they will inhibit HMG-CoAR (Schachter, 2005). Inhibition of HMG-CoAR will not only diminish the synthesis of cholesterol, but also that of ubiquinone, steroids, bile acids, vitamin D, as well as geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) (Fig. 1) (Brown, Ikonen, & Olkkonen, 2014). Statins elicit pleiotropic effects on the cardiovascular system, effects in part secondary to the Thr172 phosphorylation of AMP-activated protein kinase (AMPK) (Sun et al., 2006). Approximately 25% of the world population older than 65 years take a statin for primary or secondary prevention of cardiovascular diseases (Gu, Paulose-Ram, Burt, & Kit, 2014; Wallach-Kildemoes, Stovring, Holme Hansen, Howse, & Pétursson, 2016). Although statins are generally well tolerated, patients treated with statins may complain of diminished lower extremity muscular strength (Loenneke & Loprinzi, 2016). Moreover, statins may produce statin-induced myotoxicity (SIM), including heterogeneous clinical manifestations such as muscle weakness, muscle pain or aching (myalgia), stiffness, muscle tenderness, cramps, and arthralgia. Any of these symptoms can be presented with or without an elevation of creatine kinase (CK) serum concentrations. On the contrary, elevation of serum CK might be the only sign of SIM. The prevalence of SIM is subject of considerable discussion because the clinical reports vary widely, due to the lack of uniformity to define SIM, and because large randomized trials do not report reliable estimates of statin intolerance and furthermore, may not reflect clinical practice (Guyton et al., 2014; Muntean et al., 2017). In clinical practice, the incidence of SIM range from 7 to 29% of patients treated with statins (Cohen, Brinton, Ito, & Jacobson, 2012; Zhang et al., 2013). Recently, an international expert workshop on SIM proposed a standardization of the terminology and of the phenotypes (Alfirevic et al., 2014). Table 1 summarizes the classification of the different phenotypes of SIM. Asymptomatic elevation of serum creatine kinase (CK) (SIM 0) and mild myalgia (SIM 1) are not always associated to statins, they may be secondary to other drugs, diseases or simply to exercise. However, SIM 0 and/or SIM 1 are reported by around 30% of patients taking statins; in patients with SIM 0 and SIM 1, statins are usually not discontinued. In patients with SIM 2, the myalgia is sufficiently important to reduce patient’s quality of life, in which case, statins are

Table 1 Statin-induced myotoxicity (SIM) classification and prevalence. Adapted from Alfirevic et al., 2014. Classification Phenotype SIM 0 SIM 1 SIM 2 SIM 3 SIM 4 SIM 5 SIM 6

CK elevated b4 × ULN No myalgia CK not elevated Mild myalgia CK elevated b4 × ULN Severe myalgia CK N4 × ULNb10 × ULN Myopathy CK N10 × ULNb50 × ULN Severe myopathy CK N10 × ULN Rhabdomyolysis HMG-CoAR antibodies Autoimmune-mediated necrotizing myositis

Prevalence 1.5–26% 0.3–33% 0.02–0.2% 5/100,000 patients-year 0.11% 0.1–8.4/100,000 patients-year ~2/1,000,000 patients-year

CK creatine kinase; ULN upper limit of normal; HMG-CoAR 3-hydroxy-3-methylglutarylCoA reductase.

discontinued. More severe forms of SIM (3-5) are accompanied by various degrees of muscle necrosis, and statins are always discontinued. For SIM 2-5, the discontinuation of the statin will relieve the symptoms. The statin-induced autoimmune myopathy (SIM 6) is caused by autoantibodies against HMG-CoAR, the pharmacological target of statins; after statin discontinuation, symptoms usually persist (Stroes et al., 2015). There is some evidence supporting that in patients with SIM, plasma concentrations of statins and/or its metabolites are elevated, suggesting that pharmacokinetic mechanisms underlie SIM. Effectively, Hermann et al. (2006) reported that in patients with atorvastatin-induced SIM, plasma concentrations of o-hydroxyatorvastatin, p-hydroxyatorvastatin, atorvastatin lactone and p-hydroxyatorvastatin lactone were significantly higher than the plasma concentrations of these compounds estimated in patients without SIM. However, this is not always the case, since SIM has been reported in presence of plasma concentrations of statins in between the accepted normal range (Phillips et al., 2002). Therefore, at least two conditions must underlie SIM mechanism of action: pharmacokinetic conditions leading to statin accumulation into the muscle, and myocyte conditions favouring statin toxicity. Indeed, numerous risk factors, such as age, gender, ethnicity, frailty, genetics, presence of other diseases, and polypharmacy (Mancini et al., 2016; Stroes et al., 2015) will contribute to one or the other group of conditions. This review will first discuss the pharmacokinetic conditions that may increase statin concentrations into the myocyte, and thereafter, present the conditions in the muscle that may trigger SIM. 2. Pharmacokinetic conditions resulting in statin accumulation in the myocyte 2.1. Hepatic handling of statins

Fig. 1. Schematic representation of the mevalonate pathway

Once absorbed, statins (acid and lactone forms) have to reach the liver to elicit the desired effect, e.g. inhibit HMG-CoAR, and be eliminated by biotransformation. Statins will pass through the fenestrations of the endothelial cells, attain the space of Disse, and ultimately the hepatocytes (Fig. 2). Being organic acids, the passage of statins into the hepatocyte is mediated by membrane carriers of the solute carrier transporter (SLC) superfamily, primarily by members of the organic anion transporting polypeptide (OATP). In the hepatocyte (Fig. 3), the major influx transporters of statins are OATP1B1 (encoded by SLCO1B1 and expressed primarily in the liver and small intestine) and OATP1B3 (encoded by SLCO1B3). Less importantly, OATP2B1 (encoded by SLCO2B1) may also contribute to the influx transport of statins (see review Bosgra et al., 2014; Kunze, Huwyler, Camenisch, & Poller, 2014; Rodrigues, 2010). Other influx transporters of statins include OATP1A2

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Fig. 2. Pharmacokinetics of statins. Once absorbed, in the portal blood, statins will reach the liver, and from the space of Disse will penetrate into the hepatocyte where they will inhibit the 3-hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoAR) and be metabolized. Statins not retained in the liver will attain the systemic circulation and be distributed in many tissues, among them the muscle. Once in contact with the muscle, statins will penetrate in the myocytes, inhibit muscle HMG-CoAR in the sarcoplasma, and potentially affect muscle function.

(encoded by SLCO1A2), and sodium-dependent taurocholate cotransporting polypeptide (NTCP) (encoded by SLC10A1) (Fujino, Saito, Ogawa, & Kojima, 2005; Ho et al., 2006). In the hepatocyte, the inactive lactone forms of lovastatin and simvastatin are converted to the active β-hydroxy acid form. Statin β-hydroxy acid form is biotransformed by the cytochrome P450 isoforms CYP3A4, CYP2C9 and CYP2C8 to generate hydroxylated metabolites that also contribute to inhibit HMG-CoAR. The exception is pravastatin, mainly biotransformed by a sulfotransferase generating an inactive metabolite, 3′ α-iso pravastatin (Chauvin, Drouot, Barrail-Tran, & Taburet, 2013; Shitara & Sugiyama, 2006). Statins and metabolites are removed from the hepatocyte by means of efflux membrane transporters of the ATP-

binding cassette superfamily, primarily breast cancer resistance protein (BCRP) (encoded by ABCG2) and multidrug resistance 1 (MDR1) or Pglycoprotein (encoded by ABCB1) (Fig. 3). In addition, multidrug resistance protein 2 (MRP2) (encoded by ABCC2) and bile salt export pump (BSEP) (encoded by ABCB11) contribute to the efflux of statins and metabolites out of the hepatocyte (Chauvin et al., 2013; Rodrigues, 2010). These efflux membrane transporters are highly expressed in the membrane of the bile canalicular duct, and as a consequence, statins and their metabolites are mostly eliminated into the bile (Chauvin et al., 2013; Schachter, 2005). The concentration of statins in blood and extrahepatic organs might increase in presence of diminished activity of hepatic influx membrane

Fig. 3. Statins penetrate into the hepatocyte by means of membrane carriers, namely the organic anion transporting polypeptides (OATP) OATP1B1, OATP1B3, OATP2B1, OATP1A2, and sodium-dependent taurocholate cotransporting polypeptide (NTCP). In the hepatocyte, statins will inhibit the 3-hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and cholesterol synthesis. In the hepatocyte, statins will be biotransformed by enzymes located on the reticuloendothelial membranes, such as cytochrome P450 isoforms CYP2C8, CYP2C9 and CYP3A4. Most metabolites are active and contribute to inhibit HMG-CoA reductase. Statins and their metabolites may be expelled from the hepatocyte into the bile canalicular duct or to the blood by membrane carriers of the ATP-binding cassette superfamily, breast cancer resistance protein (BCRP), multidrug resistance 1 (MDR1) or Pglycoprotein, as well as by multidrug resistance protein 2 (MRP2), bile salt export pump (BSEP) and the organic solute transporter a or β (OSTα/β).

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transporters, primarily OATP1B1, reduced activity of the enzymes implicated in their biotransformation and finally, decreased activity of hepatic efflux membrane transporters, essentially BCRP and MDR1. The pharmacological response of the statins should be decreased in presence of reduced transport activity of OATP1B1 (Dai et al., 2015) and on the contrary, increased when the rate of influx is increased or the rates of biotransformation and efflux are diminished. Genomewide studies support an association between SLCO1B1 and ABCG2 polymorphisms and statin response (Chasman et al., 2012; Leusink, Onland-Moret, de Bakker, de Boer, & Maitland-van der Zee, 2016). Changes in the activity of membrane transporters and enzymes of biotransformation will affect the statins differently because of their distinct physico-chemical properties and the presence of redundant pathways.

2.1.1. Association between reduced function of OATP1B1 and SIM Missense variants of SLCO1B1 are associated to the incidence of SIM, primarily variant c.521T N C (rs4149056) with reduced function of OATP1B1. The prevalence of diplotypes combining the haplotypes *5, *15 and *17 (C allele) is around 5%, and encode a carrier with low function. On the other hand, the prevalence of diplotypes combining *1a and *1b (T allele) with *5, *15 or *17 is around 25%, and encode a carrier with moderate activity (Ramsey et al., 2014). The incidence of haplotype *5 in Caucasians is 3.3%, and that of the haplotype *15 in Caucasians and East Asians is 14%, and in Sub-Saharan Africans is 1.9% (Giacomini et al., 2013). SLCO1B1 missense c.521TNC variant by reducing the access of statins into the hepatocyte, diminishes their metabolic clearance and as a consequence, plasma concentrations are enhanced. In spite of increased statin plasma concentration the pharmacological response is not increased (Generaux, Bonomo, Johnson, & Doan, 2011), suggesting that alternative membrane transporters OATP2B1, OATP1A2 and NTCP are barely effective for the uptake of statins into the hepatocyte. In carriers of the variant c.521TN C with CC genotype (Table 2), the area under the plasma concentration-time curve (AUC) of active lovastatin acid and of pravastatin are 3.4 and 1.9 times greater (Maeda et al., 2006; Tornio et al., 2015), that of simvastatin and pitavastatin 3.2 fold greater (Pasanen, Neuvonen, Neuvonen, & Niemi, 2006; Zhou, Chen, et al., 2013), and that of atorvastatin, 3.1 fold greater than the AUC estimated in carriers of the TT genotype (Nies et al., 2013). In carriers of TC/CC genotype, plasma concentrations of rosuvastatin are 1.8 times higher than in carriers of TT genotype (Lee et al., 2013). On the other hand, the AUC of fluvastatin is not significantly increased in carriers of the c.521CC haplotype (Niemi, Pasanen, & Neuvonen, 2006). The go-DARTS trial showed that the SLCO1B1 c.521TN C genotype is associated with statin intolerance, odds risk (OR) 2.05 (95% C.I. 1.02– 4.09), defined as increase of serum CK or modified statin regimen, e.g. discontinuation, switching or dose-reduction (Donnelly et al., 2011). Considering statin-induced CK elevation with no or mild myalgia, patients homozygous for the C allele treated with simvastatin, atorvastatin or rosuvastatin present a significantly greater risk than the patients heterozygous or homozygous for the T allele (Ferrari et al., 2014).

Table 2 Fold increase of the area under the plasma concentration-time curve of statins in carriers of variants with low function of SLCO1B1, ABCB1 and ABCG2.

Lovastatin Simvastatin Pravastatin Fluvastatin Atorvastatin Pitavastatin Rosuvastatin

SLCO1B1 c.521TNC

ABCB1 c.1236CNT, c.2677GNT, c.3435CNT

ABCG2 c.421CNA

3.4 3.2 1.9 1.2 3.1 3.2 1.8

1.3 1.4 0.9 1.0 1.5 2.0, 0.5, 0.8 1.1

ND 1.6 0.9 1.7 1.7 1.0–1.5 2.4

ND not determined. See text for the references.

A genomewide scan documented that compared with TT homozygotes, the OR for SIM with simvastatin is 4.5 (95% C.I., 2.6 to 7.7) per copy of C allele, and 16.9 (95% C.I., 4.7–61.1) in CC; results replicated by a trial involving 10,269 patients treated with simvastatin (Link et al., 2008). The risk of SIM in carriers of the SLCO1B1 c.521TNC genotype treated with simvastatin is increased by gender (female), and is greater than with pravastatin or atorvastatin (Voora et al., 2009). In carriers of the SLCO1B1 c.521T NC variant, the probability of having to decrease the dose or to switch to another cholesterol-lowering drug is higher with simvastatin than with atorvastatin (de Keyser et al., 2014). In fact, the risk of SIM in carriers of SLCO1B1 c.521T NC genotype is low or non-existing with atorvastatin (Brunham et al., 2012; Carr et al., 2013; Santos et al., 2012), and rosuvastatin (Danik et al., 2013). A meta-analysis including 9 studies with 1360 patients with SIM and 3082 controls, reported that compared with TT carriers, the OR in TC + CC carriers to present SIM is 2.09 (95% C.I., 1.27–3.43), risk even greater with aging. When the patients are segregated function of the statin received, the OR with simvastatin is 3.09 (95% C.I., 1.64–5.85) and that of atorvastatin 1.31 (95% C.I., 0.74–2.30) (Hou et al., 2015). A recent meta-analysis including 11,246 subjects, of whom 2355 developed SIM, reported a strong association between carriers of the c.521T NC variant and simvastatin-induced SIM, but not atorvastatin (Jiang et al., 2016). 2.1.2. Association between reduced function of MDR1/P-glycoprotein and SIM The haplotype ABCB1*13 with loss of function contains the single nucleotide polymorphisms (SNP) c.1236CNT, c.2677GNT and c.3435CN T. The incidence of ABCB1*13 in Caucasians, Asian-Americans, MexicanAmericans and Pacific Islanders is 33%, and in African-Americans is 5% (Kroetz et al., 2003). Of the polymorphic variant combinations, the 3435CN T is the most relevant for the loss of function of MDR1; the synonymous SNP c.3435CN T (rs1045642) in exon 26 of ABCB1 is associated with reduced protein expression and function; the expression of MDR1 in carriers of the TT genotype is 50% lower than in subjects with the CC genotype (Kimchi-Sarfaty et al., 2007). Compared with carriers of the c.1236C-c.2677G-c.3435C haplotype, the AUCs of simvastatin acid and atorvastatin are greater in carriers of the c.1236T-c.2677T-c.3435T haplotype, but not that of fluvastatin, pravastatin, lovastatin and rosuvastatin, (Table 2) (Keskitalo, Kurkinen, Neuvonen, & Niemi, 2008; Keskitalo, Kurkinen, et al., 2009). In the Chinese population, pitavastatin AUC in c.1236T-c.2677Tc.3435T carriers is 2.0, 0.5 and 0.8 times the AUC estimated in c.1236C-c.2677G-c.3435C haplotype carriers (Zhou, Chen, et al., 2013). Several prospective studies have reported a weak association between MDR1 variants and incidence of SIM. In patients treated with simvastatin, atorvastatin, and rosuvastatin the incidence of SIM was higher in carriers of the T allele of c.3435CN T SNP (Ferrari et al., 2014; Fiegenbaum et al., 2005; Hoenig, Walker, Gurnsey, Beadle, & Johnson, 2011). A meta-analysis including 3 studies (58 cases and 239 controls) did not find a significant association between the SNP c.3435C NT and SIM; however, when only subjects treated for more than 5 months were considered, there was a strong association between carriers of the T allele and SIM (Su et al., 2015). 2.1.3. Association between reduced function of BCRP and SIM A nonsynonymous SNP, c.421C N A (rs2231142), localized in the ABCG2 ATP-binding domain, is associated with impaired BCRP activity. The allele frequency of c.421C NA varies according ethnic populations, ranging from 7.4 to 11.1% in Caucasians, 27 to 35% in East Asians, and around 1% in Sub-Saharan Africans (Giacomini et al., 2013). In Caucasians and East Asians, the AUCs of fluvastatin, simvastatin, atorvastatin and rosuvastatin (but not pravastatin) are greater in carriers of the ABCG2 c.421AA genotype than in carriers of the ABCG2 c.421CC genotype (Table 2) (Birmingham et al., 2015; Keskitalo, Pasanen, Neuvonen, & Niemi, 2009; Keskitalo, Zolk, et al., 2009; Lee et

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al., 2013; Wan et al., 2015; Zhou, Ruan, Jiang, Yuan, & Zeng, 2013; Zhou, Ruan, Yuan, Xu, & Zeng, 2013). In East Asians, compared with the c.421CC genotype, the pharmacokinetics of pitavastatin are not modified by the ABCG2 c.421AA genotype (Ieiri et al., 2007; Oh, Kim, Cho, Park, & Chung, 2013; Zhou, Chen, et al., 2013). The proportion of patients treated with simvastatin, atorvastatin and rosuvastatin with SIM tended to be greater in carriers of the ABCG2 c.421CA genotype than in carriers of the ABCG2 c.421CC genotype, e.g. 36.4 vs 18.2% (p = 0.120) (Ferrari et al., 2014). Among patients with SIM treated with atorvastatin, 61.5% were carriers of the ABCG2 c.421CA/AA genotype, compared with 38.5% (p = 0.03) in patients without SIM (Mirošević Skvrce et al., 2015). Membrane carriers other than OATP1B1, MDR1 and BCRP, may contribute to increase statin plasma concentrations and adverse effects. For instance, in healthy Chinese carriers of the SLC10A1 c.800TT/CT genotype (encoding NTCP), rosuvastatin AUC was 58% greater than in subjects with the SLC10A1 c.800CC genotype (Lou et al., 2014). Decrease of simvastatin dosage or switch to another cholesterol-lowering drug are associated with variants of the ABCC2 gene (encoding MRP2); this is not the case for atorvastatin (Becker et al., 2013). 2.1.4. Association between reduced function of cytochrome P450 isoforms and SIM The kinetics of hydrophilic statins, e.g. pravastatin and rosuvastatin, are less influenced by changes in cytochrome P450 activity than lipophilic statins, e.g. fluvastatin, simvastatin, atorvastatin and pitavastatin. Simvastatin is primarily biotransformed by CYP3A4 and minimally by CYP3A5; the expression of CYP3A4 c392ANG or CYP3A5 c.6896ANG variants do not affect the incidence of simvastatin myotoxicity (Fiegenbaum et al., 2005). Compared with the CYP3A4*1/*1 genotype, atorvastatin myotoxicity does not appear to be associated with the CYP3A4*1/*22 genotype with reduced oxidative activity (Mirošević Skvrce et al., 2015). However, the myotoxicity of atorvastatin may be associated to CYP3A5*3, a minor metabolic pathway in adults (Wilke, Moore, & Burmester, 2005). Compared with carriers of the CYP2C9*1/ *1 or the CYP2C19*1/*1 genotypes, plasma concentrations of rosuvastatin are not greater in carriers of CYP2C9*1/*3 or *3/*3 or CYP2C19*2/*2 or *2/*3 (poor metabolizers) (Lee et al., 2013). The

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STRENGTH trial did not find any association between CYP2D6*4, CYP2D6*10, CYP2C8*3, CYP2C8*4, CYP2C9*3 and CYP3A4*1b genotypes (poor metabolizers) and SIM in 99 patients treated with pravastatin, simvastatin or atorvastatin (Voora et al., 2009). Altogether, the polymorphisms of cytochrome P450 isoforms do not appear to be relevant for the incidence of SIM (Canestaro, Austin, & Thummel, 2014). 2.2. Muscular handling of statins To produce myotoxicity, statins have to penetrate and accumulate into the myocyte (Fig. 4). The sarcolemma of the myocyte expresses several influx transporters, such as OATP2B1 (Knauer et al., 2010), OATP1A2 (Banerjee et al., 2013), and OAT1/OAT2 (Burckhardt & Burckhardt, 2011). The influx of atorvastatin and rosuvastatin into the myocyte is mediated by OATP2B1 (Knauer et al., 2010), and that of pitavastatin and pravastatin is carried out by OAT1/2 and OATP1A2 (Fujino et al., 2005; Shirasaka, Suzuki, Shichiri, Nakanishi, & Tamai, 2011). The myocyte also expresses efflux transporters, such as MDR1 (Thiebaut et al., 1989), BCRP (Meyer zu Schwabedissen & Kroemer, 2011), and MRP1, MRP4, and MRP5 (Keppler, 2011; Knauer et al., 2010). Altogether, OATP1B1 is highly expressed in the liver but not in the muscle, so the SLCO1B1 c.521TNC variant will diminish the influx of a statin into the liver but not into the myocyte. On the other hand, BCRP and MDR1 are expressed in both liver and skeletal muscle, implicating that in presence of SNPs with loss of function encoding for BCRP and MDR1, statins and/or metabolites may accumulate in the myocyte. The fact that not all carriers of SLCO1B1, ABCB1 and ABCG2 polymorphisms complain of SIM, suggests that several polymorphisms must be present in the same subject or alternatively, specific muscular conditions must be present to increase the individual susceptibility to SIM. 3. Muscular mechanisms underlying the presentation of SIM The following sections will review aspects of muscle physiology relevant to SIM, the effect of statins on human muscle and finally, in vivo animal and in vitro studies highlighting different muscular mechanisms that shall contribute to the appearance of SIM.

Fig. 4. Statins pass through the sarcolemma of the myocyte by means of the membrane carriers, organic anion transporting polypeptides (OATP) OATP2B1, OATP1A2, and organic anion transporter 1 and 2 (OAT1, 2). Statins are expelled from the myocyte to the blood by membrane carriers of the ATP-binding cassette superfamily, breast cancer resistance protein (BCRP), multidrug resistance 1 (MDR1) or P-glycoprotein, as well as by multidrug resistance protein 1, 4, 5 (MRP1,4,5). The lactate membrane carrier monocarboxylate transporter 1 and 4 (MCT1,4) may also contribute to the influx and the efflux of statins from the myocyte.

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3.1. Physiology of muscle function 3.1.1. Skeletal muscle function and remodeling 3.1.1.1. Energy supply. In the myocyte, energy depends on the availability of adenosine triphosphate (ATP), primarily generated in the mitochondria. For this purpose, in the sarcoplasma, glucose and lactate are transformed into pyruvate that is transported into the mitochondria where it is oxidized to acetyl CoA by the pyruvate dehydrogenase complex (PDC). Acetyl CoA is incorporated into the tricarboxylic acid (TCA) cycle and reduced to β-nicotinamide adenine dinucleotide (NADH). NADH is oxidized by the electron transport chain of the mitochondria to originate ATP, process that requires O2, ubiquinone (CoQ10), and cytochrome c (Fig. 5) (Horscroft & Murray, 2014). By phosphorylating ADP, mitochondrial and sarcoplasmic CK may also generate ATP (Joncquel-Chevalier Curt et al., 2015; Varikmaa et al., 2014). In the sarcoplasma, the availability of glucose and lactate is regulated by the glucose transporter 4 (GLUT4) and the monocarboxylate transporter 1 (MCT1) in the sarcolemma. During muscle exercise, the decrease of ATP and increase of AMP trigger the phosphorylation of AMPK Thr172 which directly, or by means of cAMP response elementbinding protein (CREB) (Hardie & Sakamoto, 2006) or myosin enhance factor 2 (MEF2) (Egan et al., 2010), induces the transcription factor peroxisome-proliferator-activated receptor coactivator-1α (PGC-1α), that induces the expression of GLUT4 (Jäger, Handschin, St-Pierre, & Spiegelman, 2007) and MCT1 (Benton, Nickerson, et al., 2008), and increase glucose and lactate availability. Moreover, enhanced expression of PGC-1α induces lactate dehydrogenase B (LDH B) that drives the conversion of lactate to pyruvate (Summermatter, Santos, Pérez-Schindler,

& Handschin, 2013). On the other hand, when glucose availability is reduced, ketone bodies are used in the mitochondria as source of ATP, in which case, PGC-1α is an essential regulator of ketone body oxidation to generate acetyl CoA (Svensson, Albert, Cardel, Salatino, & Handschin, 2016).

3.1.1.2. Reactive oxygen species (ROS) metabolism. In the inner membrane of the mitochondria, the transport of electrons (e−) occurs in complex I (NADH:ubiquinone oxidoreductase) or in complex II (succinate:ubiquinone oxidoreductase) after the extraction of electrons from NADH or FADH2; the electrons are transferred along the respiratory chain to finally generate H2O in complex IV (cytochrome c oxidase). Simultaneously, protons (H+) are formed and pumped into the intermembrane space, where the gradient of H+ forms the inner membrane potential. During respiration, electrons leak from complex I and III (cytochrome bc1 complex) into the matrix of the mitochondria, and react with •− O2 to generate superoxide (O•− 2 ). Around 75% of mitochondrial O2 originates from the transfer of electrons from ubiquinol to cytochrome c catalyzed by complex III. Blocking mitochondrial respiration downstream complex I will increase the electron leak and O•− 2 formation. In presence of superoxide dismutase (SOD), O•− 2 is converted to H2O2 and further reduced to H2O by catalase (CAT) and glutathione peroxidase (GPx). However, H2O2 may flow outside the mitochondria into the sarcoplasma and activate redox-dependent signalling and/or cause an oxidant stress (Handy & Loscalzo, 2012). Mitochondrial ROS by inhibiting the mitochondrial permeability transition pore (mPTP) and reducing the efflux of Ca2+ from the mitochondria, protect the myocyte from death (Madungwe, Zilberstein, Feng, & Bopassa, 2016).

Fig. 5. Schematic representation of myocyte physiological response to muscle demand as potential targets of statins. To exercise, the muscle must generate energy, the main source being ATP production by the mitochondrial respiratory chain and by CK. Glucose and lactate enter the myocyte by means of channels GLUT4 and MCT1/4, respectively, and will be transformed into pyruvate, and through the TCA cycle form NADH that will be incorporated into the mitochondrial respiratory chain to yield ADP and ultimately ATP, as well as H2O and ROS (O•− 2 and H2O2). The mitochondrial respiratory chain requires O2, CoQ10 or ubiquinone, and cytochrome c. ROS activate redox-dependent signalling pathways. ROS are neutralized by SOD, and CAT. 2+ 2+ In the sarcoplasma, Ca ([Ca ]s) and end products of the mevalonate pathway (geranylgeranyl pyrophosphate) through the RhoA/PI3K/AKT/mTOR/PGC-1α pathway enhance protein synthesis, e.g. MCT1,4, GLUT4, SOD, CAT, PGK4. On the other hand, PGC-1α will inhibit apoptosis by blocking the activation of caspase 9, and proteolysis by blocking the activation of FoxO3 and that of E3 ligases MuRF-1 and MAFbx or atrogin-1, that control substrate specificity of the proteasome. The decrease of ATP and increase of AMP activate AMPK that will promote the nuclear translocation of the transcription factor PGC-1α to enhance the expression of proteins related with energy production. AMPK may also phosphorylate FoxO3 and trigger its nuclear translocation. Moreover, [Ca2+]s and ATP regulate sarcolemma ClC-1 and resting conductance. AKT protein kinase B; AMPK AMP-activated protein kinase; Bcl-2 B-cell lymphoma 2; BCRP breast cancer resistance protein; CaMKII calmodulin kinase II; CAT catalase; CK creatine kinase; ClC-1 chloride channel; FoxO3 forkhead box O3; GLUT4 glucose transporter 4; H2O2 hydrogen peroxide; HMG-CoAR 3-hydroxy-3-methylglutaryl-coenzyme A reductase; MAFbx or atrogin-1muscle atrophy F-box; MCT monocarboxylate transporter; MDR1 or Pglycoprotein multidrug resistance 1; mPTP mitochondrial permeability transition pore; mTOR mammalian target of rapamycin; MuRF-1 muscle RING-finger protein-1; O•− 2 superoxide; OATP organic anion transporting polypeptide; PDC pyruvate dehydrogenase complex; PDK piruvate dehydrogenase kinases; PGC transcription factors peroxisomeproliferator-activated receptor coactivator; RhoA Ras homolog gene family member A; ROS reactive oxygen species; SOD superoxide dismutase; SR sarcoplasmic reticulum; TCA tricarboxylic acid.

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In the muscle, O•− 2 is regulated by several mechanisms involving PGC-1α. Physiological concentrations of ROS promote the phosphorylation of AMPK Thr172, downstream activation of PGC-1α, and induction of the expression of SOD1 and SOD2. After an exercise, stimulation of the mitochondrial respiratory chain increases the production of H2O2 that in the one hand, activates p38 mitogen-activated protein kinase (p38MAPK), with subsequent phosphorylation of MEF2 (Akimoto et al., 2005; Gomez-Cabrera, Salvador-Pascual, Cabo, Ferrando, & Viña, 2015; Zhang et al., 2014), and in the other hand activates the nuclear translocation of CREB (Hashimoto, Hussien, Oommen, Gohil, & Brooks, 2007; St-Pierre et al., 2006), both triggering an up-regulation of PGC1α, and increase of the expression of SOD, CAT and GPx, that will diminish ROS concentrations. Paradoxically, pathological concentrations of ROS promote the phosphorylation of protein kinase B (AKT) and phosphorylation of AMPK Ser485/491, inhibiting AMPK Thr172 phosphorylation (Irrcher, Ljubicic, & Hood, 2009; Morales-Alamo & Calbet, 2016). 3.1.1.3. Muscle remodeling. Muscle remodeling is associated to the demand, e.g. exercising or sedentary, and includes protein synthesis, protein degradation and apoptosis. Protein synthesis is primarily dependent upon the transcription factor PGC-1α. Mitochondrial gene targets of PGC-1α are involved in oxidative phosphorylation, TCA cycle and uncoupling respiration; nuclear gene targets of PGC-1α are implicated in angiogenesis, protein synthesis, lactate and energy homeostasis. PGC-1α is regulated by AMPK and ROS, and in addition, by the mevalonate pathway and Ca2+ signaling (Hoppeler, 2016). The end-product of the mevalonate pathway GGPP prenylates and activates Ras homolog gene family member A (RhoA), that phosphorylates phosphatidylinositol 3-kinase (PI-3K), AKT and mammalian target of rapamycin (mTOR) (Bonifacio, Sanvee, Bouitbir, & Krähenbühl, 2015; Coupel, Leboeuf, Boulday, Soulillou, & Charreau, 2004), leading to the activation and nuclear transcription of PGC-1α (Fig. 5) (Cunningham et al., 2007). High sarcoplasmic Ca2+ ([Ca2+]s) activates calmodulin kinase II (CaMKII) that will phosphorylate and activate AKT, mTOR, and ultimately PGC-1α (Bonifacio et al., 2015; Gehlert, Bloch, & Suhr, 2015). On the other hand, CaMKII may also phosphorylate and activate transcription factors CREB and MEF2, and subsequently the transcription of PGC-1α (Egan et al., 2010; Smith, Kohn, Chetty, & Ojuka, 2008). Activated PGC-1α induces the nuclear receptor peroxisomeproliferator activating receptor γ (PPARγ) that increases the expression of insulin-induced gene-1 and -2 (Insig-1, -2), proteins that trigger HMG-CoAR ubiquitination and proteosomal degradation (RodrigueWay et al., 2014). In summary, PGC-1α is activated by exercise, AMPK, Ca2+, H2O2, and GGPP and as such, functions as a central fuel sensor in skeletal muscles by regulating, among other proteins, the expression of GLUT4, MTC1/4, SOD, CAT, GPx, HMG-CoAR, and mitochondrial oxidative phosphorylation (Benton, Nickerson, et al., 2008; Benton, Yoshida, et al., 2008; Handschin, 2010). Protein degradation and muscle atrophy are associated to the nuclear translocation of forkhead box O3a (FoxO3a), and the subsequent induction of genes encoding E3 ligases muscle RING-finger protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx or atrogin-1) that control substrate specificity of the proteasome (Clavel et al., 2010; Malavaki et al., 2015; Zheng, Ohkawa, Li, Roberts-Wilson, & Price, 2010). Activated AMPK Thr172 phosphorylates FoxO3a Ser588, triggering its nuclear translocation and increase of MAFbx transcription (Greer et al., 2007). On the other hand, phosphorylation of FoxO3a Thr32, Ser253, Ser315 by AKT, translocates FoxO3a protein from the nucleus to the sarcoplasma, in such a way that it diminishes the transcription of MuRF-1/MAFbx ligases and consequently, proteolysis is reduced (Malavaki et al., 2015; Wagatsuma et al., 2016). Training with resistance and endurance exercises increases the expression of AKT and reduces MAFbx allowing for exercise-muscle hypertrophy (Kazior et al., 2016). Apoptosis also contributes to muscle atrophy and remodeling. Following a mitochondrial insult, cytochrome c released into the

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sarcoplasma binds, cleaves, and activates the cysteine protease procaspase-9, generating caspase 9 that activates caspase 3, and propagates the apoptotic caspase cascade; AKT by phosphorylating caspase-9 Ser196 prevents its cleavage and activation by cytochrome c (Huang et al., 2014; Kim & Chung, 2002). 3.1.2. Mechanisms underlying muscle fatigue, myalgia and CK elevation The transmission of muscular nociception is primarily carried out by unmyelinated C fibers and by myelinated Aδ fibers (Millan, 1999). Ending of nociceptors express receptors for algesic substances, such as ATP, bradykinin, serotonin, substance P, histamine, prostaglandin E2 and capsaicin, as well as cations (Ca2+, Na+) and protons (H+) (Graven-Nielsen & Mense, 2001). Moreover, lactate stimulates group III and IV chemosensitive afferents with activation of nociceptive transmission (Rotto & Kaufman, 1988). In muscles of subjects with myalgia at rest and during exercise, the concentrations of lactate are higher than in controls without muscle pain (Rosendal et al., 2004). Intramuscular infusion of the combination of low concentrations of protons, lactate and ATP provoke fatigue, and higher concentrations of these metabolites will promote fatigue and pain (Pollak et al., 2014). Moderate increases of lactate, reduction of ATP with increases of ADP, and diminished sarcoplasmic reticulum (SR) Ca2+ pumping have been associated with muscular pain and fatigue; moreover, ROS by altering mitochondrial and/or sarcoplasmic function contribute to muscular fatigue (see reviews by Allen, Lamb, & Westerblad, 2008; Grassi, Rossiter, & Zoladz, 2015; Vandenboom, 2004). In the muscle, transport of lactate involves a lactate-proton co-transport system, MCT1 for the influx, and MCT4 for the efflux of lactate (encoded by SLC16A1 and SLC16A3, respectively), which are located in the sarcolemma, T-tubules and mitochondria (Benton, Campbell, Tonouchi, Hatta, & Bonen, 2004). The expression of MCT1 is modulated by elevated [Ca2+]s and AMP, that in turn activate the Ca2+-dependent phosphatase, calcineurin, AMPK and PGC-1α (Halestrap & Wilson, 2012). Blood lactate concentrations and fatigue after an exercise are negatively associated to the amount of MCT1 and MCT4 expressed in the muscle (Thomas et al., 2005). Subjects expressing the variant SLC16A1 c.1470T NA of MCT1 with reduction/loss of function, show higher lactate plasma concentrations and present muscle stiffness, pain or cramping after exercise (Merezhinskaya, Fishbein, Davis, & Foellmer, 2000). Genotype frequencies of c.1470T NA are 40, 47 and 13% for the TT, AT and AA genotypes (Massidda et al., 2015). Excitability of the myocyte depends, in part, on resting chloride channel conductance (gCl) regulated by the ClC-1 chloride channel. High activity of ClC-1 channels enhances gCl and stabilizes resting sarcolemma potential, allowing repolarization and muscle relaxation following an action potential. The activity of ClC-1 is reduced by ATP and protein kinase C (PKC)-dependent phosphorylation. Vigorous exercise by diminishing sarcoplasma ATP, will augment ClC-1 activity and gCl, and diminish muscle excitability, situation that may contribute to muscle fatigue (Imbrici et al., 2015; Tang & Chen, 2011) In summary, physiologically, muscular fatigue and myalgia are primarily associated with low ATP concentrations, enhanced gCl, presence of ROS, altered [Ca2 +]s metabolism, and accumulation of lactate. In healthy individuals, vigorous exercise may not only provoke muscle fatigue and pain, but may often damage the sarcomere and Z-disk, as well as the sarcolemma; perforation of the sarcolemma will facilitate CK leaking into the interstitial fluid of the muscle, and via the lymphatic system reach the circulation (Koch, Pereira, & Machado, 2014). 3.2. Effect of statins on human muscle in presence or absence of SIM In subjects treated with statins without SIM, skeletal muscle biopsies show a disruption of the structural integrity of the muscle, characterized by fiber degradation, swelling, vacuolization and disintegration of T-tubules, subsarcolemmal fissures, and Z-line deviations (Draeger et al.,

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2006). Phosphodiesters are increased in human skeletal muscle of patients without SIM, indicating that statins enhance the breakdown of sarcolemma phospholipids (Slade, Delano, & Meyer, 2006). In patients without SIM treated with simvastatin, plasma and muscle concentrations of ubiquinone are reduced by 30%, and mitochondrial activities of complexes II, III and IV are diminished by 40% (Päivä et al., 2005). In muscle biopsies from patients treated with simvastatin, muscle activity of citrate synthase is diminished, a marker of mitochondrial dysfunction, and genes involved in oxidative phosphorylation, pyruvate metabolism, TCA cycle, respiratory electron transport and ATP synthesis are down-regulated (Schick et al., 2007; Suneja et al., 2015). On the other hand, in healthy volunteers, atorvastatin does not affect mitochondrial function in muscle (Päivä et al., 2005). Although, following a vigorous exercise, atorvastatin, up-regulates genes involved in the ubiquitin proteasome system, protein folding and catabolism, and the apoptosis cascade (Urso, Clarkson, Hittel, Hoffman, & Thompson, 2005). In summary, in subjects without SIM, statins may alter the mitochondrial respiratory chain and ATP synthesis and in addition, upregulate genes involved in the ubiquitin proteasome system, effects that appear to be more severe with simvastatin than with atorvastatin. In patients with SIM but normal CK serum concentrations, muscle biopsies evidence increased lipid stores, cytochrome oxidase-negative myofibers, as well as ragged red fibers, denoting mitochondrial respiratory chain dysfunction; it is noteworthy that these lesions are observed in subjects with statin plasma concentrations within the normal range (Phillips et al., 2002). Moreover, muscle biopsies from patients with SIM show subsarcolemmal detachment of myofibrils with vacuolated T-tubules, high [Ca2+]s, and enhanced expression of the Ca2+ channels SR ryanodine receptor 3 (RYR3) and sarco-endoplasmic reticulum transporting Ca2+ ATPase 3 (SERCA3) mRNAs (Mohaupt et al., 2009). In muscle biopsies from healthy volunteers given simvastatin without myalgia but with elevated CK serum concentrations, mitochondrial respiration is reduced, and Ca2 + spark amplitude enhanced (Galtier et al., 2012). Compared with muscle biopsies from healthy subjects not exposed to statins, in muscle biopsies from patients on statins without SIM and with SIM (myalgia and elevated CK), the activity of the respiratory chain is reduced in both asymptomatic and SIM patients; however, when complex IV is specifically investigated, its activity is reduced only in patients with SIM; moreover, the amplitude of Ca2+ sparks is increased in all patients exposed to statins, but Ca2 + spark frequency is reduced only in patients with SIM (Sirvent et al., 2012). In deltoid muscle biopsies from patients with SIM, mitochondrial respiration is diminished, expression of PPARGC1A and PPARGC1B mRNAs (encoding PGC-1α, -1β) is decreased, as well as the expression of SOD1 and SOD2 mRNAs (encoding SOD1, 2) and as a consequence, H2O2 is increased. On the other hand, the pro-apoptotic Bcl-2-associated X (Bax)/anti-apoptotic B-cell lymphoma 2 (Bcl-2) ratio and apoptosis are enhanced (Bouitbir et al., 2012, 2016). Compared with control subjects not exposed to statins, in biopsies of the quadriceps femoris from patients with SIM, the activity of complex III, as well as ATP production are significantly diminished; interestingly, the ratio muscle to plasma concentration of pravastatin, rosuvastatin, atorvastatin and simvastatin was 0.82, 6, 300 and 490, respectively, emphasizing the differences between statin kinetics and that statins can cause SIM without accumulating in the muscle (Schirris et al., 2015). In quadriceps muscle biopsies from patients with SIM, the expression of MAFbx mRNA is twofold greater than in healthy volunteers and subjects with myopathy not associated with statins (Hanai et al., 2007). Altogether, in muscle biopsies of patients with SIM, mitochondrial function is altered with diminished production of ATP, excess production of ROS, and apoptosis; moreover, Ca2+ homeostasis is altered, the expression of PGC-1α/β and SOD1/2 is down-regulated, and that of MAFbx is up-regulated.

3.3. Myocyte mechanisms underlying SIM Statins reach the sarcoplasma of the myocyte by means of membrane carriers, and thereafter access to the mitochondria. Statins may damage the myocyte targeting functions in the sarcoplasma and/or in the mitochondria. It is difficult to dissociate the effect of the statins elicited in the sarcoplasma from that in the mitochondria, since the effect elicited in one compartment has repercussions in the other. In the following sections, the effect of statins that may potentially contribute to SIM will be reviewed according to the type of mechanism, indirect in the mitochondria and sarcoplasma, consequence of HMG-CoAR inhibition, or direct in the mitochondria and sarcoplasma. 3.3.1. Indirect effect of statins on muscle due to the inhibition of HMG-CoAR By inhibiting HMG-CoAR, statins diminish the formation of the metabolites of the mevalonate pathway such as ubiquinone, GGPP and FPP (Fig. 1). HMG-CoAR is expressed in skeletal muscle, and statins inhibit the mevalonate pathway in the myocyte more efficiently than in the hepatocyte (Morikawa et al., 2005). The pivotal role of the mevalonate pathway in myocyte health is illustrated by the fact that in HMG-CoAR knockout mice, myopathy develops rapidly with elevated CK serum concentrations, damage prevented by the administration of mevalonic acid (Osaki et al., 2015). Using cultured rat skeletal myotubes, it was shown that lovastatin, pravastatin and simvastatin reduce ATP and protein synthesis, effects abrogated by the addition of mevalonate (Masters et al., 1995); although the myotoxicity appears secondary to diminished geranylgeranylation of proteins (Flint, Masters, Gregg, & Durham, 1997). These early reports suggest that inhibition of HMG-CoAR by statins affects mitochondrial and sarcoplasmic functions. 3.3.1.1. Inhibition of HMG-CoAR: reduced ubiquinone and SIM. Ubiquinone is an essential coenzyme for mitochondrial respiration during the transfer of electrons between complex I and II of the respiratory chain; diminished concentrations of ubiquinone may impair mitochondrial respiration and ATP production. There is a controversy on the role of ubiquinone in SIM. In muscles of mice receiving atorvastatin, ubiquinone was reduced by almost 50% (Muraki et al., 2012). Compared with placebo, in healthy volunteers, simvastatin and atorvastatin reduce plasma ubiquinone by 30%, although only simvastatin diminishes ubiquinone concentrations, as well as mitochondrial function in the muscle (Päivä et al., 2005). In rats receiving atorvastatin, the decrease in muscle ATP and the myopathy are partially prevented by the administration of ubiquinone (El-Ganainy et al., 2016). In human rhabdomyosarcoma cells, simvastatin reduces time- and dose-dependently mitochondrial oxidative function and ATP production, as well as cell viability, effects prevented by co-treatment with ubiquinone (Vaughan, Garcia-Smith, Bisoffi, Conn, & Trujillo, 2013). Even if a recent meta-analysis supports that treatment with statins reduces plasma concentrations of ubiquinone (Banach, Serban, Sahebkar, et al., 2015; Banach, Serban, Ursoniu, et al., 2015), baseline values of plasma ubiquinone or statin-induced reduction of ubiquinone concentrations do not correlate with the presentation of SIM (Skilving, Acimovic, Rane, Ovesjö, & Björkhem-Bergman, 2015). On the other hand, squalene synthase inhibition and reduction of cholesterol, as well as ubiquinone depletion, do not induce myotube death on their own nor do enhance cerivastatin-induced cell death, supporting the fact that muscular damage is not promoted by the decrease in intracellular cholesterol or ubiquinone (Johnson et al., 2004), but by reduction of protein prenylation (Mullen, Lüscher, Scharnagl, Krähenbühl, & Brecht, 2010). 3.3.1.2. Inhibition of HMG-CoAR: effect on apoptosis. Incubation of lovastatin, pravastatin, simvastatin and atorvastatin with rat vascular smooth muscle cells promotes apoptosis, secondary to the inhibition of the prenylation of small GTPases of the Rho family, effect reverted by the addition of mevalonate, FPP or GGPP (Guijarro et al., 1998). In

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cardiac fibroblasts and myofibroblasts, simvastatin impedes geranylgeranyl prenylation and activation of small GTPases and consequently, caspase 3 is activated and apoptosis enhanced (Copaja et al., 2011). Similarly, in rat and human myotube cultures, cerivastatin, simvastatin, and a lactone structurally related to lovastatin, enhance apoptosis dose-dependently by activating caspase 3, effect prevented by mevanolate, geranylgeraniol, and less efficiently by farnesol; moreover, direct inhibition of geranylgeranyl transferase and protein isoprenylation enhances apoptosis (Johnson et al., 2004). In human rhabdomyosarcoma cells, cerivastatin and simvastatin diminish protein prenylation and cell viability, effects abrogated by mevalonate (Gee et al., 2015). 3.3.1.3. Inhibition of HMG-CoAR: effect on proteolysis. Incubation of single skeletal myofibers of rat flexor digitorium with fluvastatin or pravastatin leads to a dose-dependent formation of craters along the sarcolemma, swelling of the SR and mitochondria, and intracellular vacuoles. These lesions are abrogated by the co-incubation with GGPP but not FPP; moreover, the lesions are replicated by inhibiting Rab-small GTPase (Sakamoto, Honda, Yokoya, Waguri, & Kimura, 2007). In cultured myotubes, lovastatin enhances MAFbx, with reduction of myotube diameter, effect prevented by mevanolate and by geranylgeranol but not by farnesol; moreover, inhibition of geranylgeranyl transferase increases MAFbx, with muscle damage similar to that produced by lovastatin (Cao et al., 2009). Taken together, statin-induced muscle atrophy by apoptosis and/or proteolysis may be, at least in part, associated with a reduction of protein geranylgeranylation of small GTPases with the subsequent inhibition of the RhoA/AKT, and activation of caspase 9 and of MuRF1/ MAFbx (Fig. 5). 3.3.2. Direct effect of statins on the myocyte 3.3.2.1. Direct effect of statins on mitochondrial function. To alter mitochondrial function, statins need to access into the mitochondria. There is indirect evidence suggesting that carriers of the SLC superfamily are not expressed in the outer or inner membranes of the mitochondria (Nagasawa, Nagai, Ishimoto, & Fujimoto, 2003; Nagasawa et al., 2002). On the other hand, MCT1, MCT2 and MCT4 transporters are expressed in sub-sarcolemmal mitochondria (Benton et al., 2004; Hashimoto & Brooks, 2008), and are able to transport statins (Nagasawa et al., 2003, 2002). Therefore, we may speculate that the effect of statins on mitochondrial function depends upon their uptake by MCT1 and MCT4. 3.3.2.1.1. Depression of mitochondrial respiratory chain. Incubation of human muscle fibers from the vastus lateralis with simvastatin increases NADH, implying that simvastatin impairs mitochondrial respiratory chain with accumulation of reduced NADH; the effect of simvastatin is not reversed by a mimetic of SOD/CAT, suggesting that ROS is not the triggering effect of simvastatin (Sirvent, Mercier, Vassort, & Lacampagne, 2005). In myocytes and L6 skeletal muscle myoblasts from rats, cerivastatin, fluvastatin, simvastatin and atorvastatin, but not pravastatin, decrease mitochondrial respiration, fatty acid oxidation and membrane potential, and increase mitochondrial swelling, as well as the release of cytochrome c into the sarcoplasma; the depression of mitochondrial respiration is due to the inhibition of the electron transport chain, and uncoupling of oxidative phosphorylation (Kaufmann et al., 2006). In C2C12 myotubes, simvastatin reduces mitochondrial membrane potential and oxygen consumption (Mullen et al., 2011). In vastus lateralis muscle fibers, simvastatin alters maximal ADP-stimulated oxygen consumption of the mitochondrial respiratory function, but not basal or maximal uncoupled mitochondrial respiration, supporting that simvastatin impairs mitochondrial respiration at complex I and/or III; in addition, by inhibiting complex III, simvastatin increases mitochondrial production of O•− 2 (Kwak et al., 2012). Incubation of C2C12

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myoblasts with the acid and lactone forms of several statins decreases basal oxygen consumption rate, as well as maximal respiration of complex I, II, and glycerol-3-phosphate dehydrogenase driven respiration, with reduction of ATP production; statins by docking directly into the Qo site of complex III, inhibit ubiquinol:cytochrome c oxidoreductase activity, and complex III driven respiration. The lactone form is more potent than the acid form, and atorvastatin, cerivastatin, lovastatin and simvastatin are stronger inhibitors than pitavastatin, pravastatin and rosuvastatin (Schirris et al., 2015). In plantaris muscle of rats receiving atorvastatin, mitochondrial DNA, cytochrome oxidase 1, nuclear respiratory factor 1, and maximal mitochondrial respiration are reduced. Moreover, ROS are increased, while SOD and reduced glutathione are diminished; these alterations are prevented by quercetin (Bouitbir et al., 2012). 3.3.2.1.2. Dysregulation of Ca2+ metabolism. In rats, fluvastatin and atorvastatin elevate [Ca2 +]s in fibers of the fast-twitch extensor digitorum longus muscle, increase not associated to enhanced sarcolemmal cationic permeability; in vitro, fluvastatin increases the release of Ca2 + from the mitochondria through the mPTP and the increase in [Ca2 +]s activates an additional release of Ca2 + from the SR through the RyR channel (Liantonio et al., 2007). In human skeletal muscle fibers, simvastatin enhances [Ca 2 +] s, result of an early release of Ca2 + from the mitochondria through mPTP and Na+-Ca2 + exchanger (NCE) channels, and a late efflux associated to the uptake of [Ca 2 +] s by SERCA and release by the SR Ca 2 + channel RyR; GGPP, FPP or mevalonate, or a SOD/CAT mimetic do not prevent simvastatin induced increase in [Ca2 +]s, suggesting that opening of mPTP and NCE channels results from the decrease of mitochondrial membrane potential and depolarization of the inner mitochondrial membrane (Sirvent et al., 2005). Altogether, statins alter mitochondrial electron transport chain by directly inhibiting complexes I and III, effects that reduce the availability of ATP and mitochondrial membrane potential, and enhance ROS. Moreover, statins increase [Ca2+]s primarily by opening mPTP and NCE channels, and secondarily by release of Ca2 + from the SR through RyR channels. The opening of mPTP and NCE channels may be due to the decrease of mitochondrial membrane potential, and not to the increase of ROS or the decrease in GGPP, FPP or mevalonate. It is tempting to speculate that the decrease of ATP in the myocyte may affect the activity of the efflux transporters of the ATP binding cassette family MDR1 and BCRP, favoring the accumulation of statins into the myocyte. 3.3.2.2. Direct effect of statins on muscle remodeling 3.3.2.2.1. Statins promote apoptosis. Incubation of C2C12 myoblasts with atorvastatin, cerivastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin promotes apoptosis (Schirris et al., 2015). Statins may enhance apoptosis through two mechanisms, e.g. mitochondrial damage or inhibition of the RhoA/AKT cascade. Statins by decreasing mitochondrial membrane potential, open the mPTP channel and as a consequence, cytochrome c is released from the mitochondrial intermembrane space into the sarcoplasma where it initiates the apoptotic cascade (Kaufmann et al., 2006). Contributing to the release of cytochrome c, simvastatin induces the expression of pro-apoptotic Bax known to increase mPTP opening and cytochrome c release, with the subsequent activation of caspase 9 and caspase 3 and myotube apoptosis (Kwak et al., 2012). Similar results are observed with atorvastatin that enhances the Bax/Bcl-2 ratio, caspase 3 activity and apoptosis in glycolytic skeletal muscle (plantaris) of rats and in L6 myoblasts (Bouitbir et al., 2016). In muscle of mice receiving simvastatin, RhoA and AKT phosphorylation are reduced, and as a consequence the cleavage of caspase 9 and 3 is increased with activation of the apoptotic cascade (Bonifacio et al., 2015). In C2C12 myotubes, simvastatin prevents AKT T308 phosphorylation by insulin growth factor-1 (IGF-1), suggesting that simvastatin inhibits the IGF-1R/PI3K pathway; addition of IGF-1 suppresses muscle atrophy and apoptosis and restores protein synthesis (Bonifacio, Sanvee, et al., 2016).

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3.3.2.2.2. Statins activate E3 ubiquitin ligases 3.3.2.2.2.1. Effect of statins on RhoA/AKT/PGC-1α pathway. In C2C12 myotubes, lovastatin, simvastatin and atorvastatin (not rosuvastatin) decrease AKT and FoxO3 Ser253 phosphorylation, and therefore enhance nuclear translocation of FoxO3 and its binding to MAFbx promoter, with the subsequent increase of MAFbx mRNA and muscle atrophy; overexpression of PGC-1α prevents lovastatin-induced muscle atrophy (Bonifacio et al., 2015; Hanai et al., 2007). The protective effect of PGC-1α on statin-induced atrophy is explained by the fact that PGC1α directly impedes FoxO3 binding to the promoter of MAFbx gene (Sandri et al., 2006). In vivo in rats, simvastatin reduces phosphorylated AKT, FoxO1 and FoxO3 in the sarcoplasma, and increases FoxO1 and FoxO3 in nuclear fractions; in parallel, the expression of MAFbx and MuRF-1 mRNA is elevated, with muscle fiber necrosis and elevated serum CK (Mallinson, Constantin-Teodosiu, Sidaway, Westwood, & Greenhaff, 2009). 3.3.2.2.2.2. Effect of statins on AMPK. Statins may activate AMPK and induce muscle proteolysis by means of several redundant mechanisms. In H9c2 cells (rodent cardiomyocyte cell line), simvastatin impairs mitochondrial electron transport chain and reduces the concentrations of ATP, with the subsequent activation of the energy sensor AMPK, that phosphorylates FoxO3a Ser588, activates its nuclear translocation, and enhances atrogin-1 expression (Bonifacio, Mullen, et al., 2016; Jaitovich et al., 2015). In bovine aortic endothelial cells, by increasing ROS, simvastatin activates PKCζ-Thr410/403, liver kinase B1-Ser428, and AMPK Thr172 (Choi et al., 2008). In arterial preparations of mice receiving simvastatin, increased [Ca2+]s activates Ca2+/Calmodulin-dependent Kinase Kinase (CaMKK) that promotes AMPK Thr172 phosphorylation (Kou, Sartoretto, & Michel, 2009). Altogether, statins can promote proteolysis by diminishing AKT activation and FoxO3 Ser253 phosphorylation, in such a way that FoxO3 can translocate to the nuclei and induce the expression of MAFbx and MuRF-1. In addition, statin-induced muscle atrophy may be caused by enhanced AMPK Thr172 and FoxO3 Ser588 phosphorylation, nuclear translocation of FoxO3 Ser588 and induction of the expression of MAFbx and MuRF-1. 3.3.2.3. Direct effect of statins on sarcoplasma chloride and lactate. In rats receiving fluvastatin or atorvastatin, resting chloride conductance (gCl) in the extensor digitorum longus muscle diminishes by 30%, due to a decrease of ClC-1 mRNA expression. Moreover, statins by increasing [Ca2+]s, activate PKCθ that phosphorylates ClC-1 channel and reduces its activity. Reduction of CLC-1 channel activity and gCl can cause muscle cramps and myalgia (Camerino et al., 2016; Pierno et al., 2009). Interestingly, CLCN1 gene p.R894* variant encodes a ClC-1 channel with reduced function that is more frequent in patients with SIM than in a control population, with an OR 2.83 (95% C.I. 0.99–8.09; p = 0.04) (Neřoldová et al., 2016). In skeletal muscle, lactate/proton cotransport by MCT1 and MCT4 is bidirectional, e.g. facilitate lactate flux, relative to lactate concentration and the proton gradient (H+), either into or out of the myocyte. The high affinity MCT1 is predominantly expressed in oxidative type I fibers, whereas the low affinity MCT4 is mostly expressed in fast twitch glycolytic type II muscle fibers (Bonen, 2001). The expression of MCT1 is regulated by AMPK and PGC-1α, and that of MCT4 by AMPK; MCT1 appears more actively involved in the uptake of lactate, whereas MCT4 in the cellular efflux of lactate (Benton, Yoshida, et al., 2008; Halestrap & Wilson, 2012; Kitaoka et al., 2014). MCT1 and MCT4 are expressed in the sarcolemmal and the mitochondrial membranes (Benton et al., 2004). Carriers of missense mutations of MCT1 may present muscle cramps, fatigue and elevations of serum CK with exercise (Merezhinskaya et al., 2000). The uptake of lovastatin acid into rat mesangial and bovine kidney BNL-1 cells is pH dependant and carried out mostly by MCT4, and secondarily by MCT1; moreover, lovastatin acid dose-dependently inhibits

lactic acid uptake by MCT4 (Nagasawa et al., 2003, 2002). In human rhabdomyosarcoma cells, pravastatin inhibits MCT1 uptake and MCT4 efflux of lactic acid by 42% and 21%, respectively (Kobayashi, Fujita, Itagaki, Hirano, & Iseki, 2005). In human LLC-PK1 cells transfected with MCT4, lovastatin, simvastatin, cerivastatin, fluvastatin, and atorvastatin inhibit lactic acid uptake with an IC50 lower than 100 μM, while pravastatin and rosuvastatin IC50 is greater than 100 μM (Kobayashi, Otsuka, Itagaki, Hirano, & Iseki, 2006). Cerivastatin, simvastatin, fluvastatin and atorvastatin inhibit MCT4 uptake of L-lactate, and reduce cell viability dose-dependently; the decrease in cell viability by cerivastatin is associated to increased activity of caspase3/7; incubation of cerivastatin with bicarbonate raises intracellular pH and almost normalizes caspase 3/7 activity (Kobayashi, 2015). Similar observation was carried out with simvastatin and atorvastatin, but not pravastatin (Kobayashi et al., 2012). The authors concluded that statin-induced muscle injury is associated with intracellular acidification due to the accumulation of lactate following the inhibition of MCT4. It is noteworthy that knockdown of MCT4 with siRNA, prevents cell death and caspase-3/7 activation by atorvastatin, simvastatin and fluvastatin, indicating that statin myotoxicity is not associated to lactate accumulation into the cells (Kikutani et al., 2016). Since there is evidence that statin uptake by MCT4 is pH-dependent, e.g. basic/physiologic pH diminish considerably the uptake (Nagasawa et al., 2003), we are tempted to speculate that adding bicarbonate and blocking MCT4 protein expression reduce the uptake and concentration of statins into the cell and/or mitochondria, and as a consequence, reduce statin myotoxicity. Taken together, statins increase lactate concentrations in the sarcoplasma, probably by blocking MCT1/4 and in addition, reduce resting chloride conductance by blocking ClC-1 channels, effects that can produce muscular fatigue and cramps. 4. Prevention/treatment of SIM Detailed description of the management of SIM is not within the scope of the present revision, therefore readers are referred to the European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management of SIM (Stroes et al., 2015). Drug-drug interactions may account for almost 50% of SIM, most of interactions occurring at the level of membrane carriers BCRP, MDR1 and OATP1B1, and cytochrome P450, e.g. CYP3A4; therefore, when statins are prescribed, careful consideration to concomitant medication must be given (see reviews of Causevic-Ramosevac & Semiz, 2013; Gluba-Brzozka, Franczyk, Toth, Rysz, & Banach, 2016; Saxon & Eckel, 2016; Thai et al., 2016). Exercise and hypothyroidism might also contribute to the advent and severity of SIM (Saxon & Eckel, 2016). Keeping in mind that frequently there is a family history of SIM, that the prevalence of SIM is higher in women, and that SIM is dose-dependent (Karalis et al., 2016; Skilving, Eriksson, Rane, & Ovesjö, 2016), the dose of statins should be titrated gradually in patients with family history of SIM, and particularly in women. Even if family studies suggest a strong genetic component in SIM, pharmacogenetic tests to predict SIM may only be relevant for simvastatin regarding SLCO1B1 521TN C variant (Kitzmiller, Mikulik, Dauki, Murkherjee, & Luzum, 2016), since other rare variants in genetic predisposition are unlikely (Stránecký et al., 2016). The patients with metabolic syndrome, particularly those with elevated triglyceride concentrations and low high density lipoprotein-cholesterol (HDL-C) concentrations, may be predisposed to present SIM (Brinton, Maki, Jacobson, Sponseller, & Cohen, 2016). Alcohol intake (≥30 g/day in men and ≥20 g/day in women) appears an independent factor associated with SIM (Pedro-Botet, Millán Núñez-Cortés, Chillarón, Flores-Le Roux, & Rius, 2016), and patients should be advised to reduce ethanol consumption. The response to coenzyme Q10 supplements to avoid and/or reduce SIM is conflicting; some studies report an improvement of SIM

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(Skarlovnik, Janić, Lunder, Turk, & Šabovič, 2014), but other conclude that coenzyme Q10 supplements do not reduce SIM (Taylor, Lorson, White, & Thompson, 2015). A recent systematic review and meta-analysis suggests that coenzyme Q10 supplements do not modify myalgia or CK serum concentrations (Banach, Serban, Sahebkar, et al., 2015; Banach, Serban, Ursoniu, et al., 2015). Statin-induced decreases of ubiquinone are not associated with the presentation of SIM and as a consequence, current guidelines do not recommend coenzyme Q10 supplements for patients treated with statins (Stroes et al., 2015). In rats, the increase of proteasome activity and myopathy observed following the administration of simvastatin is blunted by the administration of dichloroacetate (DCA), a pyruvate dehydrogenase complex (PDC) activator; activation of PDC allows to overcome the inhibition of PDC by PDK4 (Mallinson et al., 2012). Since DCA has already been given to humans (Mori, Yamagata, Goto, Saito, & Momoi, 2004), it might be of interest to investigate whether DCA can prevent SIM. Inhibition of HMG-CoAR will reduce the synthesis of 7dehydrocholesterol, the precursor of vitamin D (Fig. 1) (Brown et al., 2014). Since patients with vitamin D deficiency present proximal myalgia and fatigue (Girgis, Clifton-Bligh, Hamrick, Holick, & Gunton, 2013), it was hypothesized that patients with low plasma concentrations of vitamin D might be at higher risk to present SIM. A recent retrospective cohort study demonstrated an association between low vitamin D plasma concentrations (b15 ng/ml) and SIM (Palamaner Subash Shantha, Ramos, Thomas-Hemak, & Pancholy, 2014). Moreover, a cross-sectional study found that patients with vitamin D plasma concentrations b15 ng/ml had two fold greater odds to present SIM (Morioka, Lee, Bertisch, & Buettner, 2015). In a retrospective medical record review of 450 patients who were prescribed simvastatin, myalgia was reported by 50 patients with serum concentrations of 25(OH) D3 of 26 ± 9 ng/ml compared with concentrations of 36 ± 12 ng/ml in patients without muscle complains (Mergenhagen, Ott, Heckman, Rubin, & Kellick, 2014). Two systematic review and meta-analysis report a strong association between 25(OH) D3 serum levels b30 ng/ml and SIM (Michalska-Kasiczak et al., 2015; Pereda & Nishishinya, 2016). Carriers of the vitamin D receptor variant c.1056T NC have four times greater risk to develop SIM (Ovesjö et al., 2016). In vitamin D deficient patients with SIM, administration of high doses of vitamin D (50,000 IU/week) improves the myalgia and moreover, most patients on statin rechallenge tolerate the statin (Linde, Peng, Desai, & Feldman, 2010). In 146 patients with myalgia, myositis, myopathy, or myonecrosis with at least two statins, and a median serum vitamin D concentration of 23 ng/ml, given 50,000–100,000 IU/week of vitamin D, when challenged with statins, 86% of patients were SIM free at 6 months, and 95% of patients tolerated the statin at 24 months (Khayznikov et al., 2015). Patients with SIM and receiving 50,000–100,000 IU/week of vitamin D improve significantly without signs of hypervitaminosis D (Jetty et al., 2016). It is worth noting that vitamin D deficiency presents some similarities with some mechanisms of action underlying SIM. In vitamin D depleted mice, quadriceps muscle fibers are smaller and grip strength is significantly weaker than in their controls; in muscle, myostatin and MuRF1 mRNA are increased, and Serca 2 and 3 mRNA are reduced (Girgis et al., 2015). In C2C12 skeletal myotubes, 1,25(OH)2D3 enhances AKT and mTOR phosphorylation and protein synthesis dose-dependently (Salles et al., 2013), effects partially dependent on the presence of the vitamin D receptor (Buitrago, Pardo, & Boland, 2013). Accordingly, low concentrations of vitamin D diminish AKT phosphorylation and enhance myostatin and MuRF1 mRNA, besides a probable alteration of [Ca2+]s metabolism secondary to the down-regulation of Serca mRNA. Vitamin D deficiency in the myocyte might be additive to the mechanisms underlying SIM. Since treatment with statins appear not to reduce plasma concentrations of vitamin D (Sahebkar et al., 2016), supplements of high dosages of vitamin D may be helpful to avoid SIM in patients with initially plasma concentrations of vitamin D lower than 30 ng/ml.

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Under a strict clinical point of view, in patients with high cardiovascular risks, when low density lipoprotein-cholesterol (LDL-C) concentrations remain above recommended therapeutic target because of the presence of SIM, the use of inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9), monoclonal antibodies is highly effective, and does not appear to produce myotoxicity (Robinson et al., 2015; Sabatine et al., 2015). Future encouraging approaches include the use of a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of PCSK9 (Fitzgerald et al., 2017). On the other hand, the use of cholesterol cholesteryl ester transfer protein (CETP) inhibitors remains controversial (Hovingh, Ray, & Boekholdt, 2015).

5. Conclusions Since SIM is dose-dependent, it has been assumed that high blood concentrations of statins are required to precipitate SIM. Blood concentrations of statins may be increased in carriers of variants of influx transporters such as SLCO1B1, and efflux transporters such as ABCB1 and ABCG2. Indeed, SIM has been associated with the loss/decrease of function of these transporters. However, SIM may be present in patients with normal blood statin concentrations. The fact that many patients with transporter variants do not present SIM implicates that increased concentrations of statins in the myocyte may not be sufficient to trigger SIM. Therefore, the presence of specific conditions in the muscle facilitating SIM are also required, e.g. myocyte and extra-myocyte conditions have to coexist in the same individual to initiate SIM. In the myocyte, several concomitant mechanisms may contribute to SIM. Once in the sarcoplasma (Fig. 6), statins inhibit HMG-CoAR and as a consequence, may diminish geranylgeranyl prenylation of RhoA, and AKT phosphorylation, effects that promote apoptosis and FoxO3 nuclear translocation with increased expression of MAFbx and MuRF1, and proteolysis. In addition, statins by means of AMPK activation further promote FoxO3 nuclear translocation. Moreover, decreased phosphorylation of AKT will diminish PGC-1α translocation and reduce the expression of SOD, CAT, GPx, MCT1/4 and GLUT4. On the other hand, direct inhibition of sarcolemma MCT1/4 and ClC-1 channels by statins will enhance sarcoplasmic concentrations of lactate and reduce gCl, respectively. Whenever the statins access the mitochondria, by binding to complexes I and III, the mitochondrial respiratory chain will be disrupted with decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+, phenomena that will contribute to activate AMPK, proteolysis and apoptosis. Indeed, many conditions must be present in the same patient to present SIM, including genetic and epigenetic polymorphisms of multiple proteins implicated in drug transport and metabolism, as well as in the normal function of the myocyte. Co-morbidities and drug-drug interactions will facilitate the appearance of SIM. Clinically, raised [Ca2+]s, lactate, and ROS, and reduced ATP and gCl may contribute to produce fatigue, cramps and pain. Muscle remodeling due to apoptosis and proteolysis with damage of the sarcolemma membrane will elevate serum CK. Possibly, pravastatin, rosuvastatin and pitavastatin may be less prone to produce SIM than simvastatin, atorvastatin, fluvastatin and lovastatin (Silva et al. 2006; Teng et al., 2015). Management of patients with SIM include challenge with low total dosages of pravastatin, rosuvastatin and pitavastatin, and supplements of high dosages of vitamin D for those patients with low plasma concentrations of 25(OH) D3, e.g. b30 ng/ml.

Conflict of interest statement The authors declare that there are no conflicts of interest

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Fig. 6. Schematic representation of the effect of statins in the myocyte leading potentially to myotoxicity. In the sarcoplasma, statins inhibit HMG-CoAR and diminish GGPP, effect that will reduce RhoA prenylation and activation, and AKT phosphorylation, favoring the nuclear translocation of FoxO3, as well as the expression of atrogin-1 and MuRF1, with proteolysis. In the mitochondria, statins by binding to complexes I and III, disrupt the mitochondrial respiratory chain with decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+, phenomena that will contribute to activate AMPK, the nuclear translocation of FoxO3, proteolysis and apoptosis. Reduced activation of AKT will also diminish PGC-1α translocation leading to diminished expression of SOD, CAT, GPx, MCT1/4 and GLUT4, as well as binding of FoxO3 Ser588 to its DNA targets. On the other hand, inhibition of MCT4 and ClC-1 channel by statins will enhance sarcoplasmic concentrations of lactate and muscle excitability by reducing gCl. Increased sarcoplasmic Ca2+, ROS and lactate, with reduced ATP and gCl shall cause fatigue, cramps and muscle pain, and increased proteolysis, apoptosis and ROS by damaging the sarcolemma will increase blood concentrations of CK. AKT protein kinase B; AMPK AMP-activated protein kinase; Bcl-2 B-cell lymphoma 2; CaMKK Ca2+/Calmodulin-dependent Kinase Kinase; CK creatine kinase; ClC-1 chloride channel; CoQ10 ubiquinone; Cyt c cytochrome c; FoxO3 forkhead box O3; gCl resting chloride channel conductance; GGPP geranylgeranyl pyrophosphate; GLUT4 glucose transporter 4; HMG-CoAR 3-hydroxy-3-methylglutaryl-coenzyme A reductase; MAFbx or atrogin-1 muscle atrophy F-box; MCT monocarboxylate transporter; mPTP mitochondrial permeability transition pore; mTOR mammalian target of rapamycin; MuRF-1 muscle RING-finger protein-1; PDK piruvate dehydrogenase kinases; PGC transcription factors peroxisome-proliferator-activated receptor coactivator; RhoA Ras homolog gene family member A; ROS reactive oxygen species; SOD superoxide dismutase.

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