Effects of fluvastatin and coenzyme Q10 on skeletal muscle in normo- and hypercholesterolaemic rats
Myalgia and muscle weakness may appreciably contribute to the poor adherence to statin therapy. Although the pathomechanism of statin-induced myopathy is not completely understood, changes in calcium homeostasis and reduced coenzyme Q10 levels are hypothesized to play important roles. In our experiments, fluvastatin and/or coenzyme Q10 was administered chronically to normocholesterolaemic or hypercholaestherolaemic rats, and the modifications of the calcium homeostasis and the strength of their muscles were investigated. While hypercholesterolaemia did not change the frequency of sparks, fluvastatin increased it on muscles both from normocholesterolaemic and from hypercholesterolaemic rats. This effect, however, was not mediated by a chronic modification of the ryanodine receptor as shown by the unchanged ryanodine binding in the latter group. While coenzyme Q10 supplementation significantly reduced the frequency of the spontaneous calcium release events, it did not affect their amplitude and spatial spread in muscles from fluvastatin-treated rats. This indicates that coenzyme Q10 supplementation prevented the spark frequency increasing effect of fluvastatin without having a major effect on the amount of calcium released during individual sparks. In conclusion, we have found that fluvastatin, independently of the cholesterol level in the blood, consistently and specifically increased the frequency of calcium sparks in skeletal muscle cells, an effect which could be prevented by the addition of coenzyme Q10 to the diet. These results support theories favouring the role of calcium handling in the pathophysiology of statin-induced myopathy and provide a possible pathway for the protective effect of coenzyme Q10 in statin treated patients symptomatic of this condition.
KeywordsSkeletal muscle Calcium homeostase Force Spark Statin Q10 Myopathy
This work was supported by grants from the Hungarian Scientific Research Found (OTKA K 81923), from the Hungarian Ministry of Human Resources (TÁMOP-4.2.1/B-09/1/KONV-2010-0007, TÁMOP-4.2.2/B-10/1-2010-0024, and TÁMOP-4.2.2.A-11/1/KONV-2012-0025). This research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program’ (DB, VJ).
- EFSA Panel on Dietetic Products, Nutrition and Allergies (2010) Scientific Opinion on the substantiation of health claims related to coenzyme Q10 and contribution to normal energy-yielding metabolism (ID 1508, 1512, 1720, 1912, 4668), maintenance of normal blood pressure (ID 1509, 1721, 1911), protection of DNA, proteins and lipids from oxidative damage (ID 1510), contribution to normal cognitive function (ID 1511), maintenance of normal blood cholesterol concentrations (ID 1721) and increase in endurance capacity and/or endurance performance (ID 1913) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J 8(10):1793Google Scholar
- Lanner JT, Georgiou DK, Dagnino-Acosta A, Ainbinder A, Cheng Q, Joshi AD, Chen Z, Yarotskyy V, Oakes JM, Lee CS, Monroe TO, Santillan A, Dong K, Goodyear L, Ismailov II, Rodney GG, Dirksen RT, Hamilton SL (2012) AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat Med 18(2):244–251PubMedCentralPubMedCrossRefGoogle Scholar
- Lukács B, Sztretye M, Almássy J, Sárközi S, Dienes B, Mabrouk K, Simut C, Szabó L, Szentesi P, De Waard M, Ronjat M, Jóna I, Csernoch L (2008) Charged surface area of maurocalcine determines its interaction with the skeletal ryanodine receptor. Biophys J 95(7):3497–3509PubMedCentralPubMedCrossRefGoogle Scholar
- Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380(9841):581–590PubMedCrossRefGoogle Scholar
- Schaefer WH, Lawrence JW, Loughlin AF, Stoffregen DA, Mixson LA, Dean DC, Raab CE, Yu NX, Lankas GR, Frederick CB (2004) Evaluation of ubiquinone concentration and mitochondrial function relative to cerivastatin-induced skeletal myopathy in rats. Toxicol Appl Pharmacol 194(1):10–23PubMedCrossRefGoogle Scholar