Atherosclerosis 239 (2015) 38e42
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Inhibition of xanthine oxidase to prevent statin-induced myalgia and rhabdomiolysis Rafael Alis a, b, 1, Fabian Sanchis-Gomar a, c, d, 1, Jennifer Risso-Ballester a, b, Carme Perez-Quilis a, Jose Cortell-Ballester e, Marco Romagnoli a, f, Jose R. Blesa a, b, Enzo Emanuele g, * rtir, Valencia, Spain ~ a Giner”, Molecular and Mitochondrial Medicine, Catholic University of Valencia San Vicente Ma Research Institute “Dr. Vin rtir, Valencia, Spain School of Medicine, Catholic University of Valencia San Vicente Ma Department of Physiology, University of Valencia, Valencia, Spain d n Investigacio n Hospital Clínico Universitario/INCLIVA, Valencia, Spain Fundacio e Department of Anesthesiology, Hospital La Fe, Valencia, Spain f Department of Physical Education and Sports, University of Valencia, Valencia, Spain g Living Research s.a.s., Via Monte Grappa, 13, I-27038, Robbio, PV, Italy a
b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 November 2014 Received in revised form 23 December 2014 Accepted 30 December 2014 Available online 31 December 2014
Although statins remain the cornerstone of lipid-lowering therapy for reducing the burden of atherosclerotic vascular disease, their administration has been associated with muscle-related adverse effects, including myalgia and rhabdomyolysis. Such adverse events are probably due to reduced antioxidant defenses associated with fewer intermediate metabolites in the cholesterol synthesis pathway. We hypothesize that the concomitant inhibition of xanthine oxidase via coadministration of allopurinol with statins could diminish reactive oxygen species (ROS)-related muscle damage, which would have in turn have positive effects on both the incidence of muscle-related adverse events and cardiovascular outcomes. Accordingly, inhibition of xanthine oxidase has been previously shown to be effective for reducing biomarkers of muscle damage following exercise in professional athletes. Because of the widespread statin utilization and increasing trends in their therapeutic use in atherosclerotic vascular diseases, the proposed strategy could have important clinical implications for reducing statin-induced myalgia and rhabdomyolysis. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lipid-lowering drugs Myalgia Rhabdomyolysis Xanthine oxidase Allopurinol
1. Introduction Hypercholesterolemia is defined as the elevation of total cholesterol and/or low-density lipoprotein (LDL) cholesterol. This condition leads to the development of atheromatous plaques and a concomitant increase in the risk of Coronary Artery Disease (CAD), which remains a leading cause of mortality and morbidity [1]. In this scenario, total and LDL cholesterol lowering remains the mainstay for reducing the global burden of CAD. One of the main therapeutic approaches for lipid lowering is the pharmacological inhibition of cholesterol synthesis [2]. Statins are drugs that inhibit a key enzyme in cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Such an inhibition reduces * Corresponding author. E-mail address: [email protected] (E. Emanuele). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.055 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
the synthesis of cholesterol and increases the number of LDL receptors in hepatocytes, ultimately resulting in lowered total and LDL cholesterol serum levels [3]. Mevalonate is produced in a reaction catalyzed by the enzyme HMG-CoA reductase. The statininduced reduced synthesis of mevalonate not only affects cholesterol biosynthesis, but also other metabolites that are dependent on this pathway (Fig. 1). Accordingly, levels of ubiquinone (involved in mitochondrial electron transport) [4], farnesyl (FPP) and geranylgeranylpyrophosphate (GGPP) (involved in protein prenylation) [4] and isopentylpyrophosphate (required for selenocysteine tRNA maturation and thus for selenoprotein expression) are all reduced by statin administration [5]. By lowering circulating cholesterol levels, statins have been shown to effectively reduce mortality and morbidity from cardiovascular disease (CVD) [6]. Because of the high incidence of hyperlipidemia in industrialized countries, statins are widely prescribed drugs with an estimated 200 million people currently
R. Alis et al. / Atherosclerosis 239 (2015) 38e42
39
(ROS) in myotubes, ultimately resulting in cellular disruption and muscle injury, an effect clearly enhanced by exercise. Xanthine oxidoreductase (XO) activity is indeed one of the main sources of ROS during exercise and its inhibition by allopurinol has been shown to diminish circulating biomarkers of muscle damage [28e30]. Statin use does not seem to have a direct effect on XO activity and/or expression. In this regard, rosuvastatin administration for 4 weeks did not affect serum uric acid levels in patients with chronic heart failure [31]. Therefore, we hypothesize that the concomitant treatment of statin-treated patients with allopurinol would diminish exercise-induced cellular and muscle tissue damage (Fig. 2). To our knowledge, this possibility has not been sufficiently explored. 3. Discussion of the hypothesis The actions of statins on the cholesterol synthesis pathway have important consequences on cellular defenses against ROS that could be improved via XO inhibition by allopurinol. 3.1. Reduced selenoprotein levels
Fig. 1. Surrogate effects of statins on cholesterol synthesis pathway. HMG-CoA: 3hydroxy-3-methyl-glutaryl coenzyme A. PP: pyrophosphate.
under therapy worldwide [7,8]. Notably, physical exercise combined with statin use has been shown to exert synergistic protective effects against cardiovascular mortality [9,10]. Although statins are generally safe and well-tolerated, they are not without side effects. In addition to their well-known cardiovascular effects, these drugs produce non-cardiovascular effects [11] that may result in muscle toxicity [12]. In this regard, statin use has been associated with myopathy characterized by skeletal muscle pain (myalgia), inflammation (myositis), and muscle necrosis (rhabdomyolysis), especially in subjects who maintain an active lifestyle [13e21]. Notably, physical exercise has been clearly associated with an increased likelihood of developing statin-induced myopathy [22]. In addition, myalgias induced by statins have been frequently reported in physically active elderly people [23e25]. The clinical spectrum of statin-induced myopathy ranges from asymptomatic elevations in serum creatine kinase (CK) without muscle pain or weakness to rhabdomyolysis with severe muscle symptoms, accompanied by high levels of serum CK and potential kidney damage [25]. Although the underlying mechanisms of statininduced myotoxicity are not entirely understood, the development of muscle-related adverse events remains a serious issue for statintreated patients. A recent study demonstrated that 10% of patients treated with statins show muscle symptoms, including pain (87%), muscle stiffness (62%), cramps (67%), and loss of strength during exercise (55%), ultimately leading to treatment discontinuation in 30% of all cases [26]. Such muscle-related adverse events may reduce treatment adherence over time [27], ultimately increasing atherosclerotic vascular risk and the global burden of CVD.
Enzymatic isopentenylation of selenocysteine tRNA is essential for its maturation and for the self-expression of selenoproteins [32]. This process is achieved with the isopentenyl-tRNA transferase enzyme, which uses isopentenylpyrophosphate (IPP), an intermediate product of the cholesterol synthesis pathway, as a substrate [33]. The inhibitory effect of statins on HMG-CoA reductase causes a reduction in levels of IPP, which in turn results in a decreased expression of selenoproteins [5]. Glutathione peroxidases are a subfamily of selenoproteins involved in H2O2-dependent signaling, detoxification of hydroperoxides, and maintenance of cellular redox homeostasis [34]. Selenoprotein N is an important protein involved in muscle regeneration [35]. In vitro experiments have shown that treatment with statins decreases the expression of selenoproteins in myoblasts and also causes a reduction in antioxidant capacity, resulting in a decreased cell viability [36]. This effect of statin therapy is perhaps partly responsible for the damage induced by exercise on muscle tissue, by decreasing antioxidant capacity in myoblasts and slowing regeneration processes [37]. Hence, it is plausible that the inhibition of XO by allopurinol and the concomitant decrease of ROS production during exercise could help to maintain redox homeostasis.
2. Hypothesis The effects of statins on cholesterol biosynthesis cause a significant decrease in the defenses against reactive oxygen species
Fig. 2. Hypothesized mechanism of action of allopurinol in the prevention of exerciseinduced myalgia and rhabdomyolysis in statin treated patients. ROS: reactive oxygen species.
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R. Alis et al. / Atherosclerosis 239 (2015) 38e42
3.2. Reduced ubiquinone levels It has been shown that inhibition of HMG-CoA reductase by statins decreases circulating levels of ubiquinone (CoQ10) [38]. CoQ10 is an essential component in the mitochondrial electron transport chain and plays a key role in the redox equilibrium. Reduced levels of CoQ10 induced by statins caused an increased oxidative stress in vitro and in vivo, which may be partially reversed by the administration of ubiquinol [39]. In vitro experiments on muscle cells were treated with simvastatin have shown a reduction in oxidative metabolism, mitochondrial content, and cell viability, which were reverse by administration of ubiquinol [40]. In an animal model, treatment with atorvastatin reduced physical resistance through mitochondrial dysfunction related to CoQ10 deficiency [41]. In both animal and human studies, treatment with atorvastatin has been shown to result in increased ROS production in tissues such as the myocardium and the skeletal muscle [42]. Interestingly, the oxidative stress induction appears to trigger opposite effects in such tissues. In the myocardium, ROS seem to induce a positive adaptive response by increasing the expression of peroxisome proliferatoractivated receptor gamma coactivator 1-alpha (PGC-1a) [42], whereas ROS production seems to block its expression in skeletal muscle [42]. Moreover, a decreased mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) content ratio was found in the skeletal muscle of patients with statin-induced myopathy [43]. Therefore, the protective effects of allopurinol administration against ROS production might be beneficial to both mitochondrial content and function. 4. How the hypothesis should be checked To test our hypothesis, studies aimed at investigating both the cellular mechanism involved and the clinical impact of allopurinol coadministation in patients receiving statins are warranted, especially in presence of a regular physical activity. An adequate animal model should be initially established to determine the molecular consequences of allopurinol and statin coadministration, in association with the potential confounding effect of exercise. It will also be paramount to establish the impact of allopurinol-statins coadministration on exercise performance, ROS and selenoprotein levels, mitochondrial density, ubiquinone levels, ROS biomarkers, and muscle damage biomarkers. Once the molecular effects of allopurinol treatment in a model of statin-induced myopathy have been elucidated, an experimental phase on human patients should be planned in order to ascertain the clinical effects of our therapeutic strategy. To this aim, a double-blind randomized clinical trial of allopurinol coadministration (either with or without an exercise training period) should be conducted in initially drug-free, de novo statin-treated patients. The impact of the coadministration on exercise performance, muscular pain, and circulating muscle damage biomarkers should be investigated before and after the treatment period. Further studies on the pharmacological interactions of both drugs in animal models (either with or without exercise) are also necessary. For instance, it would be desirable to evaluate whether allopurinol and statins exhibit any interaction during their catabolic pathways. Similarly, it would be interesting to ascertain whether allopurinol distribution in muscle tissue could be affected by muscle fiber typology or training status. 5. Previous data supporting the hypothesis Exhaustive or acute physical exercise has been shown to cause an increased production of ROS in muscle and other organs, which finally results in cellular injury [44]. Xanthine oxidoreductase is an
intracellular enzyme that catalyzes the reduction of hypoxanthine and xanthine to uric acid [45]. Xanthine oxidoreductase exists in two interconvertible forms, xanthine dehydrogenase and XO. It uses molecular oxygen as an electron acceptor to form a superoxide anion or to reduce hypoxanthine to xanthine and then to uric acid. XO activity during exercise is one of the main sources of ROS and muscle damage [46,47]. Previous studies have shown that inhibition of XO activity by allopurinol treatment decreases ROS production during exercise and concomitant muscle damage. The administration of allopurinol in professional cyclists yielded a decrease in serum markers of muscle damage in a time-trial stage during a major professional cycling race [29]. In professional soccer players (a sport which requires eccentric contractions and, therefore, greater muscular tissue damage), allopurinol treatment prior to a match resulted in decreased ROS production and circulating levels of muscle damage biomarkers [28]. 6. Clinical implications Since 1998, the proportion of the population aged 45 years under statin therapy has been steadily increasing in both the United States [48] and Europe [49]. Moreover, the American College of Cardiology (ACC) and the American Heart Association (AHA) continue to recommend exercise and statin treatment to reduce the burden of atherosclerosis and CVD [10,50]. What is worrisome is that the 2013 guidelines published by ACC and AHA recommend the treatment of hypercholesterolemia as the primary method of preventing CVD. Extrapolating that to a concrete population (i.e. 115.4 million adult subjects living in the USA, aged 40e75 years), the number of subjects that might be treated with statins would increase to 12.9 million, mostly of them without overt CVD [51,52]. It is conceivable that such a high use of statins may result in high rates of muscle damage, especially in physically active individuals. The use of allopurinol-statin cotreatment has the goal of diminishing the deleterious effects of statin monotherapy on skeletal muscle tissue, ultimately reducing muscle-related side effects and improving treatment adherence. Besides providing benefits to muscle tissues, this strategy could enhance statin drug effects and allow the combination of statin treatment and exercise interventions to reduce the global burden of atherosclerotic vascular disorders. Single nucleotide polymorphisms of genes involved in the transport, metabolism, and clearance of statins may be associated with an increased risk of myotoxicity [53]. If our hypothesis that allopurinol could prevent the deleterious effects of statin on muscles is correct, we postulate that patients more prone to develop statin-related adverse events would especially benefit from the proposed approach. Although there is evidence that the coadministration of statins may increase the risk of suffering allopurinolrelated adverse events [54], we cannot exclude that the benefits of allopurinol coadministration might outweigh the potential risks of developing adverse effects. Further studies are needed to clarify this potential issue. Due to the high impact of dyslipidemia and statin use in industrialized countries, cotreatment with statins and allopurinol could have a huge impact on healthcare costs, ultimately reducing the incidence of statin-induced muscle adverse effects. In this regard, besides being a low-cost drug, allopurinol associated with statin may also reduce the pharmaceutical expenditure associated with simple non-opioid analgesics. Conflict of interests The authors declare no conflicts of interest.
R. Alis et al. / Atherosclerosis 239 (2015) 38e42
Acknowledgments This research has been supported by grant DEP2012-37494 from the Spanish Government and by grants 2013-168-002 and 2012011-001 from the Catholic University of Valencia. RA is a predoctoral fellow in the Catholic University of Valencia. Abbreviations ACC American College of Cardiology AHA American Heart Association CAD Coronary Artery Disease CK creatine kinase CoQ10 ubiquinone HMG-CoA 3-hydroxy-3-methyl-glutaryl coenzyme A LDL low density lipoprotein mtDNA mitochondrial DNA nDNA nuclear DNA PGC-1a Peroxisome proliferator-activated receptor gamma coactivator 1-alpha PP pyrophosphate ROS reactive oxygen species VO2max maximal oxygen uptake XO xanthine oxidoreductase References [1] A.S. Go, D. Mozaffarian, V.L. Roger, et al., Executive summary: heart disease and stroke statisticse2013 update: a report from the American Heart Association, Circulation 127 (2013) 143e152. [2] V. Tiwari, M. Khokhar, Mechanism of action of anti-hypercholesterolemia drugs and their resistance, Eur. J. Pharmacol. 741c (2014) 156e170. [3] H. Matsuyama, K. Sato, Y. Nakamura, et al., Modulation of regulatory factors involved in cholesterol metabolism in response to feeding of pravastatin- or cholesterol-supplemented diet in chickens, Biochim. Biophys. Acta 1734 (2005) 136e142. [4] J. Grunler, J. Ericsson, G. Dallner, Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins, Biochim. Biophys. Acta 1212 (1994) 259e277. [5] G.J. Warner, M.J. Berry, M.E. Moustafa, et al., Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine, J. Biol. Chem. 275 (2000) 28110e28119. [6] M. Jasinska, J. Owczarek, D. Orszulak-Michalak, Statins: a new insight into their mechanisms of action and consequent pleiotropic effects, Pharmacol. Rep. 59 (2007) 483e499. [7] M.J. Blaha, S.S. Martin, How do statins work?: changing paradigms with implications for statin allocation, J. Am. Coll. Cardiol. 62 (2013) 2392e2394. [8] G. Lippi, E.J. Favaloro, F. Sanchis-Gomar, Venous thrombosis associated with HMG-CoA reductase inhibitors, Semin. Thromb. Hemost. 39 (2013) 515e532. [9] E. Stamatakis, M. Hamer, P. Primatesta, Cardiovascular medication, physical activity and mortality: cross-sectional population study with ongoing mortality follow-up, Heart 95 (2009) 448e453. [10] N.J. Stone, J.G. Robinson, A.H. Lichtenstein, et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines, J. Am. Coll. Cardiol. 63 (2014) 2889e2934. [11] C.S. Desai, S.S. Martin, R.S. Blumenthal, Non-cardiovascular effects associated with statins, BMJ 349 (2014) g3743. [12] D.J. Graham, J.A. Staffa, D. Shatin, et al., Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs, JAMA 292 (2004) 2585e2590. [13] A.K. Kearns, C.L. Bilbie, P.M. Clarkson, et al., The creatine kinase response to eccentric exercise with atorvastatin 10 mg or 80 mg, Atherosclerosis 200 (2008) 121e125. [14] L.H. Opie, Exercise-induced myalgia may limit the cardiovascular benefits of statins, Cardiovasc. Drugs Ther. 27 (2013) 569e572. [15] S.J. Semple, Statin therapy, myopathy and exerciseea case report, Lipids Health Dis. 11 (2012) 40. [16] H. Sinzinger, J. O'Grady, Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems, Br. J. Clin. Pharmacol. 57 (2004) 525e528. [17] P.D. Thompson, J.M. Zmuda, L.J. Domalik, et al., Lovastatin increases exerciseinduced skeletal muscle injury, Metabolism 46 (1997) 1206e1210. [18] C. Buettner, R.B. Davis, S.G. Leveille, et al., Prevalence of musculoskeletal pain and statin use, J. Gen. Intern. Med. 23 (2008) 1182e1186.
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Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Inhibition of xanthine oxidase to prevent statin-induced myalgia and rhabdomiolysis Rafael Alis a, b, 1, Fabian Sanchis-Gomar a, c, d, 1, Jennifer Risso-Ballester a, b, Carme Perez-Quilis a, Jose Cortell-Ballester e, Marco Romagnoli a, f, Jose R. Blesa a, b, Enzo Emanuele g, * rtir, Valencia, Spain ~ a Giner”, Molecular and Mitochondrial Medicine, Catholic University of Valencia San Vicente Ma Research Institute “Dr. Vin rtir, Valencia, Spain School of Medicine, Catholic University of Valencia San Vicente Ma Department of Physiology, University of Valencia, Valencia, Spain d n Investigacio n Hospital Clínico Universitario/INCLIVA, Valencia, Spain Fundacio e Department of Anesthesiology, Hospital La Fe, Valencia, Spain f Department of Physical Education and Sports, University of Valencia, Valencia, Spain g Living Research s.a.s., Via Monte Grappa, 13, I-27038, Robbio, PV, Italy a
b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 22 November 2014 Received in revised form 23 December 2014 Accepted 30 December 2014 Available online 31 December 2014
Although statins remain the cornerstone of lipid-lowering therapy for reducing the burden of atherosclerotic vascular disease, their administration has been associated with muscle-related adverse effects, including myalgia and rhabdomyolysis. Such adverse events are probably due to reduced antioxidant defenses associated with fewer intermediate metabolites in the cholesterol synthesis pathway. We hypothesize that the concomitant inhibition of xanthine oxidase via coadministration of allopurinol with statins could diminish reactive oxygen species (ROS)-related muscle damage, which would have in turn have positive effects on both the incidence of muscle-related adverse events and cardiovascular outcomes. Accordingly, inhibition of xanthine oxidase has been previously shown to be effective for reducing biomarkers of muscle damage following exercise in professional athletes. Because of the widespread statin utilization and increasing trends in their therapeutic use in atherosclerotic vascular diseases, the proposed strategy could have important clinical implications for reducing statin-induced myalgia and rhabdomyolysis. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lipid-lowering drugs Myalgia Rhabdomyolysis Xanthine oxidase Allopurinol
1. Introduction Hypercholesterolemia is defined as the elevation of total cholesterol and/or low-density lipoprotein (LDL) cholesterol. This condition leads to the development of atheromatous plaques and a concomitant increase in the risk of Coronary Artery Disease (CAD), which remains a leading cause of mortality and morbidity [1]. In this scenario, total and LDL cholesterol lowering remains the mainstay for reducing the global burden of CAD. One of the main therapeutic approaches for lipid lowering is the pharmacological inhibition of cholesterol synthesis [2]. Statins are drugs that inhibit a key enzyme in cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Such an inhibition reduces * Corresponding author. E-mail address: [email protected] (E. Emanuele). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.055 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
the synthesis of cholesterol and increases the number of LDL receptors in hepatocytes, ultimately resulting in lowered total and LDL cholesterol serum levels [3]. Mevalonate is produced in a reaction catalyzed by the enzyme HMG-CoA reductase. The statininduced reduced synthesis of mevalonate not only affects cholesterol biosynthesis, but also other metabolites that are dependent on this pathway (Fig. 1). Accordingly, levels of ubiquinone (involved in mitochondrial electron transport) [4], farnesyl (FPP) and geranylgeranylpyrophosphate (GGPP) (involved in protein prenylation) [4] and isopentylpyrophosphate (required for selenocysteine tRNA maturation and thus for selenoprotein expression) are all reduced by statin administration [5]. By lowering circulating cholesterol levels, statins have been shown to effectively reduce mortality and morbidity from cardiovascular disease (CVD) [6]. Because of the high incidence of hyperlipidemia in industrialized countries, statins are widely prescribed drugs with an estimated 200 million people currently
R. Alis et al. / Atherosclerosis 239 (2015) 38e42
39
(ROS) in myotubes, ultimately resulting in cellular disruption and muscle injury, an effect clearly enhanced by exercise. Xanthine oxidoreductase (XO) activity is indeed one of the main sources of ROS during exercise and its inhibition by allopurinol has been shown to diminish circulating biomarkers of muscle damage [28e30]. Statin use does not seem to have a direct effect on XO activity and/or expression. In this regard, rosuvastatin administration for 4 weeks did not affect serum uric acid levels in patients with chronic heart failure [31]. Therefore, we hypothesize that the concomitant treatment of statin-treated patients with allopurinol would diminish exercise-induced cellular and muscle tissue damage (Fig. 2). To our knowledge, this possibility has not been sufficiently explored. 3. Discussion of the hypothesis The actions of statins on the cholesterol synthesis pathway have important consequences on cellular defenses against ROS that could be improved via XO inhibition by allopurinol. 3.1. Reduced selenoprotein levels
Fig. 1. Surrogate effects of statins on cholesterol synthesis pathway. HMG-CoA: 3hydroxy-3-methyl-glutaryl coenzyme A. PP: pyrophosphate.
under therapy worldwide [7,8]. Notably, physical exercise combined with statin use has been shown to exert synergistic protective effects against cardiovascular mortality [9,10]. Although statins are generally safe and well-tolerated, they are not without side effects. In addition to their well-known cardiovascular effects, these drugs produce non-cardiovascular effects [11] that may result in muscle toxicity [12]. In this regard, statin use has been associated with myopathy characterized by skeletal muscle pain (myalgia), inflammation (myositis), and muscle necrosis (rhabdomyolysis), especially in subjects who maintain an active lifestyle [13e21]. Notably, physical exercise has been clearly associated with an increased likelihood of developing statin-induced myopathy [22]. In addition, myalgias induced by statins have been frequently reported in physically active elderly people [23e25]. The clinical spectrum of statin-induced myopathy ranges from asymptomatic elevations in serum creatine kinase (CK) without muscle pain or weakness to rhabdomyolysis with severe muscle symptoms, accompanied by high levels of serum CK and potential kidney damage [25]. Although the underlying mechanisms of statininduced myotoxicity are not entirely understood, the development of muscle-related adverse events remains a serious issue for statintreated patients. A recent study demonstrated that 10% of patients treated with statins show muscle symptoms, including pain (87%), muscle stiffness (62%), cramps (67%), and loss of strength during exercise (55%), ultimately leading to treatment discontinuation in 30% of all cases [26]. Such muscle-related adverse events may reduce treatment adherence over time [27], ultimately increasing atherosclerotic vascular risk and the global burden of CVD.
Enzymatic isopentenylation of selenocysteine tRNA is essential for its maturation and for the self-expression of selenoproteins [32]. This process is achieved with the isopentenyl-tRNA transferase enzyme, which uses isopentenylpyrophosphate (IPP), an intermediate product of the cholesterol synthesis pathway, as a substrate [33]. The inhibitory effect of statins on HMG-CoA reductase causes a reduction in levels of IPP, which in turn results in a decreased expression of selenoproteins [5]. Glutathione peroxidases are a subfamily of selenoproteins involved in H2O2-dependent signaling, detoxification of hydroperoxides, and maintenance of cellular redox homeostasis [34]. Selenoprotein N is an important protein involved in muscle regeneration [35]. In vitro experiments have shown that treatment with statins decreases the expression of selenoproteins in myoblasts and also causes a reduction in antioxidant capacity, resulting in a decreased cell viability [36]. This effect of statin therapy is perhaps partly responsible for the damage induced by exercise on muscle tissue, by decreasing antioxidant capacity in myoblasts and slowing regeneration processes [37]. Hence, it is plausible that the inhibition of XO by allopurinol and the concomitant decrease of ROS production during exercise could help to maintain redox homeostasis.
2. Hypothesis The effects of statins on cholesterol biosynthesis cause a significant decrease in the defenses against reactive oxygen species
Fig. 2. Hypothesized mechanism of action of allopurinol in the prevention of exerciseinduced myalgia and rhabdomyolysis in statin treated patients. ROS: reactive oxygen species.
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3.2. Reduced ubiquinone levels It has been shown that inhibition of HMG-CoA reductase by statins decreases circulating levels of ubiquinone (CoQ10) [38]. CoQ10 is an essential component in the mitochondrial electron transport chain and plays a key role in the redox equilibrium. Reduced levels of CoQ10 induced by statins caused an increased oxidative stress in vitro and in vivo, which may be partially reversed by the administration of ubiquinol [39]. In vitro experiments on muscle cells were treated with simvastatin have shown a reduction in oxidative metabolism, mitochondrial content, and cell viability, which were reverse by administration of ubiquinol [40]. In an animal model, treatment with atorvastatin reduced physical resistance through mitochondrial dysfunction related to CoQ10 deficiency [41]. In both animal and human studies, treatment with atorvastatin has been shown to result in increased ROS production in tissues such as the myocardium and the skeletal muscle [42]. Interestingly, the oxidative stress induction appears to trigger opposite effects in such tissues. In the myocardium, ROS seem to induce a positive adaptive response by increasing the expression of peroxisome proliferatoractivated receptor gamma coactivator 1-alpha (PGC-1a) [42], whereas ROS production seems to block its expression in skeletal muscle [42]. Moreover, a decreased mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) content ratio was found in the skeletal muscle of patients with statin-induced myopathy [43]. Therefore, the protective effects of allopurinol administration against ROS production might be beneficial to both mitochondrial content and function. 4. How the hypothesis should be checked To test our hypothesis, studies aimed at investigating both the cellular mechanism involved and the clinical impact of allopurinol coadministation in patients receiving statins are warranted, especially in presence of a regular physical activity. An adequate animal model should be initially established to determine the molecular consequences of allopurinol and statin coadministration, in association with the potential confounding effect of exercise. It will also be paramount to establish the impact of allopurinol-statins coadministration on exercise performance, ROS and selenoprotein levels, mitochondrial density, ubiquinone levels, ROS biomarkers, and muscle damage biomarkers. Once the molecular effects of allopurinol treatment in a model of statin-induced myopathy have been elucidated, an experimental phase on human patients should be planned in order to ascertain the clinical effects of our therapeutic strategy. To this aim, a double-blind randomized clinical trial of allopurinol coadministration (either with or without an exercise training period) should be conducted in initially drug-free, de novo statin-treated patients. The impact of the coadministration on exercise performance, muscular pain, and circulating muscle damage biomarkers should be investigated before and after the treatment period. Further studies on the pharmacological interactions of both drugs in animal models (either with or without exercise) are also necessary. For instance, it would be desirable to evaluate whether allopurinol and statins exhibit any interaction during their catabolic pathways. Similarly, it would be interesting to ascertain whether allopurinol distribution in muscle tissue could be affected by muscle fiber typology or training status. 5. Previous data supporting the hypothesis Exhaustive or acute physical exercise has been shown to cause an increased production of ROS in muscle and other organs, which finally results in cellular injury [44]. Xanthine oxidoreductase is an
intracellular enzyme that catalyzes the reduction of hypoxanthine and xanthine to uric acid [45]. Xanthine oxidoreductase exists in two interconvertible forms, xanthine dehydrogenase and XO. It uses molecular oxygen as an electron acceptor to form a superoxide anion or to reduce hypoxanthine to xanthine and then to uric acid. XO activity during exercise is one of the main sources of ROS and muscle damage [46,47]. Previous studies have shown that inhibition of XO activity by allopurinol treatment decreases ROS production during exercise and concomitant muscle damage. The administration of allopurinol in professional cyclists yielded a decrease in serum markers of muscle damage in a time-trial stage during a major professional cycling race [29]. In professional soccer players (a sport which requires eccentric contractions and, therefore, greater muscular tissue damage), allopurinol treatment prior to a match resulted in decreased ROS production and circulating levels of muscle damage biomarkers [28]. 6. Clinical implications Since 1998, the proportion of the population aged 45 years under statin therapy has been steadily increasing in both the United States [48] and Europe [49]. Moreover, the American College of Cardiology (ACC) and the American Heart Association (AHA) continue to recommend exercise and statin treatment to reduce the burden of atherosclerosis and CVD [10,50]. What is worrisome is that the 2013 guidelines published by ACC and AHA recommend the treatment of hypercholesterolemia as the primary method of preventing CVD. Extrapolating that to a concrete population (i.e. 115.4 million adult subjects living in the USA, aged 40e75 years), the number of subjects that might be treated with statins would increase to 12.9 million, mostly of them without overt CVD [51,52]. It is conceivable that such a high use of statins may result in high rates of muscle damage, especially in physically active individuals. The use of allopurinol-statin cotreatment has the goal of diminishing the deleterious effects of statin monotherapy on skeletal muscle tissue, ultimately reducing muscle-related side effects and improving treatment adherence. Besides providing benefits to muscle tissues, this strategy could enhance statin drug effects and allow the combination of statin treatment and exercise interventions to reduce the global burden of atherosclerotic vascular disorders. Single nucleotide polymorphisms of genes involved in the transport, metabolism, and clearance of statins may be associated with an increased risk of myotoxicity [53]. If our hypothesis that allopurinol could prevent the deleterious effects of statin on muscles is correct, we postulate that patients more prone to develop statin-related adverse events would especially benefit from the proposed approach. Although there is evidence that the coadministration of statins may increase the risk of suffering allopurinolrelated adverse events [54], we cannot exclude that the benefits of allopurinol coadministration might outweigh the potential risks of developing adverse effects. Further studies are needed to clarify this potential issue. Due to the high impact of dyslipidemia and statin use in industrialized countries, cotreatment with statins and allopurinol could have a huge impact on healthcare costs, ultimately reducing the incidence of statin-induced muscle adverse effects. In this regard, besides being a low-cost drug, allopurinol associated with statin may also reduce the pharmaceutical expenditure associated with simple non-opioid analgesics. Conflict of interests The authors declare no conflicts of interest.
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