Skip to main content
SpringerLink
Log in

Effects of fluvastatin and coenzyme Q10 on skeletal muscle in normo- and hypercholesterolaemic rats

  • Original Paper
  • Published:
Journal of Muscle Research and Cell Motility Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Antons KA, Williams CD, Baker SK, Phillips PS (2006) Clinical perspectives of statin-induced rhabdomyolysis. Am J Med 119:400–409

    Article  CAS  PubMed  Google Scholar 

  • Banach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, Toth PP, Jones SR, Rizzo M, Glasser SP, Lip GY, Dragan S, Mikhailidis DP (2015) Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc 90(1):24–34

    Article  CAS  PubMed  Google Scholar 

  • Bookstaver DA, Burkhalter NA, Hatzigeorgiou C (2012) Effect of coenzyme Q10 supplementation on statin-induced myalgias. Am J Cardiol 110(4):526–529

    Article  CAS  PubMed  Google Scholar 

  • Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B (2005) Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 19(6):403–414

    Article  CAS  PubMed  Google Scholar 

  • Csernoch L, Szentesi P, Sárközi S, Szegedi C, Jóna I, Kovács L (1999) Effects of tetracaine on sarcoplasmic calcium release in mammalian skeletal muscle fibres. J Physiol 515(3):843–857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Daugird AJ, Crowell K, Saseen J (2003) Clinical inquiries. Do statins cause myopathy? J Fam Pract 52:973–977

    PubMed  Google Scholar 

  • 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):1793

    Google Scholar 

  • Evans CD, Eurich DT, Lamb DA, Taylor JG, Jorgenson DJ, Semchuk WM, Mansell KD, Blackburn DF (2009) Retrospective observational assessment of statin adherence among subjects patronizing different types of community pharmacies in Canada. J Manag Care Pharm 15(6):476–484

    PubMed  Google Scholar 

  • Fernandez G, Spatz ES, Jablecki C, Phillips PS (2011) Statin myopathy: a common dilemma not reflected in clinical trials. Clevel Clin J Med 78(6):393–403

    Article  Google Scholar 

  • Füzi M, Palicz Z, Vincze J, Cseri J, Szombathy Z, Kovács I, Oláh A, Szentesi P, Kertai P, Paragh G, Csernoch L (2012) Fluvastatin-induced alterations of skeletal muscle function in hypercholesterolaemic rats. J Muscle Res Cell Motil 32(6):391–401

    Article  PubMed  Google Scholar 

  • Gerber BL (2013) In vivo evaluation of atherosclerotic plaque inflammation and of anti-inflammatory effects of statins by 18F-fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 62(10):918–920

    Article  PubMed  Google Scholar 

  • Glauert AM, Dingle JT, Lucy JA (1962) Action of saponin on biological cell membranes. Nature 196:953–955

    Article  CAS  Google Scholar 

  • Guarini G, Marzilli M (2013) Defining the role of high-dose statins in PCI. Am J Cardiovasc Drugs 3:189–197

    Article  Google Scholar 

  • Herrmann-Frank A, Richter M, Sarközi S, Mohr U, Lehmann-Horn F (1996) 4-Chloro-m-cresol, a potent and specific activator of the skeletal muscle ryanodine receptor. Biochim Biophys Acta 1289(1):31–40

    Article  PubMed  Google Scholar 

  • Inoue R, Tanabe M, Kono K, Maruyama K, Ikemoto T, Endo M (2003) Ca2+-releasing effect of cerivastatin on the sarcoplasmic reticulum of mouse and rat skeletal muscle fibers. J Pharmacol Sci 93(3):279–288

    Article  CAS  PubMed  Google Scholar 

  • Isaeva EV, Shkryl VM, Shirokova N (2005) Mitochondrial redox state and Ca2+ sparks in permeabilized mammalian skeletal muscle. J Physiol 565(Pt 3):855–872

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jackevicius CA, Mamdani M, Tu JV (2002) Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 288(4):462–467

    Article  PubMed  Google Scholar 

  • Johnson TE, Zhang X, Bleicher KB, Dysart G, Loughlin AF, Schaefer WH, Umbenhauer DR (2004) Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone. Toxicol Appl Pharmacol 200(3):237–250

    Article  CAS  PubMed  Google Scholar 

  • Knoblauch M, Dagnino-Acosta A, Hamilton SL (2013) Mice with RyR1 mutation (Y524S) undergo hypermetabolic response to simvastatin. Skelet Muscle 3(1):22

    Article  PubMed Central  PubMed  Google Scholar 

  • Kon M, Kimura F, Akimoto T, Tanabe K, Murase Y, Ikemune S, Kono I (2007) Effect of Coenzyme Q10 supplementation on exercise-induced muscular injury of rats. Exerc Immunol Rev 13:76–88

    PubMed  Google 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):244–251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Littlefield N, Beckstrand RL, Luthy KE (2014) Statins’ effect on plasma levels of coenzyme Q10 and improvement in myopathy with supplementation. J Am Assoc Nurse Pract 26(2):85–90

    PubMed  Google Scholar 

  • Löhn M, Fürstenau M, Sagach V, Elger M, Schulze W, Luft FC, Haller H, Gollasch M (2000) Ignition of calcium sparks in arterial and cardiac muscle through caveolae. Circ Res 87(11):1034–1039

    Article  PubMed  Google Scholar 

  • Lotteau S, MacDougall D, Steele D, Calaghan S (2015) Statin induced myopathy: a role for mitochondrial Ca2D and no in enhanced sarcoplasmic reticulum Ca2+ Leak. Biophys J 108(2):567a

    Article  Google 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):3497–3509

    Article  PubMed Central  PubMed  Google Scholar 

  • Marcoff L, Thompson PD (2007) The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 49(23):2231–2237

    Article  CAS  PubMed  Google 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):581–590

    Article  CAS  PubMed  Google Scholar 

  • Nakahara K, Kuriyama M, Sonoda Y, Yoshidome H, Nakagawa H, Fujiyama J, Higuchi I, Osame M (1998) Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol Appl Pharmacol 152(1):99–106

    Article  CAS  PubMed  Google Scholar 

  • Oddoux S, Brocard J, Schweitzer A, Szentesi P, Giannesini B, Brocard J, Fauré J, Pernet-Gallay K, Bendahan D, Lunardi J, Csernoch L, Marty I (2009) Triadin deletion induces impaired skeletal muscle function. J Biol Chem 284(50):34918–34929

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Padra JT, Seres I, Oláh A, Fenyvesi F, Paragh G, Paragh G, Csernoch L, Fóris G, Kertai P (2014) A comparative study on dyslipidaemia inducing diets in various rat strains. Acta Physiol Hung 101(2):250–258

    Article  CAS  PubMed  Google Scholar 

  • Päivä H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimäki T, von Bergmann K, Lütjohann D, Laaksonen R (2005) High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 78(1):60–68

    Article  PubMed  Google Scholar 

  • Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M (2005) Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells. J Pharmacol Exp Ther 314(3):1032–1041

    Article  CAS  PubMed  Google Scholar 

  • Salarieh A, Soler AP, Axiotis CA (2004) Overexpression of neural cell adhesion molecule in regenerative muscle fibers in 3-hydroxy-3-methylglutaryl coenzyme: a reductase inhibitor-induced rhabdomyolysis. Appl Immunohistochem Mol Morphol 12(3):234–239

    Article  CAS  PubMed  Google Scholar 

  • Sárközi S, Szegedi C, Lukács B, Ronjat M, Jóna I (2005) Effect of gadolinium on the ryanodine receptor/sarcoplasmic reticulum calcium release channel of skeletal muscle. FEBS J 272(2):464–471

    Article  PubMed  Google 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):10–23

    Article  CAS  PubMed  Google Scholar 

  • Sirvent P, Mercier J, Vassort G, Lacampagne A (2005) Simvastatin triggers mitochondria-induced Ca2 + signaling alteration in skeletal muscle. Biochem. Biophys. Res. Commun. 329(3):1067–1075

    Article  CAS  PubMed  Google Scholar 

  • Sirvent P, Fabre O, Bordenave S, Hillaire-Buys D, Raynaud De Mauverger E, Lacampagne A, Mercier J (2012) Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins. Toxicol Appl Pharmacol 259(2):263–268

    Article  CAS  PubMed  Google Scholar 

  • Skarlovnik A, Janić M, Lunder M, Turk M, Šabovič M (2014) Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study. Med Sci Monit 20:2183–2188

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Somodi S, Balajthy A, Szilágyi O, Pethő Z, Harangi M, Paragh G, Panyi G, Hajdu P (2013) Analysis of the K+ current in human CD4+ T lymphocytes in hypercholesterolemic state. Cell Immunol 281(1):20–26

    Article  CAS  PubMed  Google Scholar 

  • Szabó LZ, Vincze J, Csernoch L, Szentesi P (2010) Improved spark and ember detection using stationary wavelet transforms. J Theor Biol 264(4):1279–1292

    Article  PubMed  Google Scholar 

  • Szegedi C, Sárközi S, Herzog A, Jóna I, Varsányi M (1999) Calsequestrin: more than ‘only’ a luminal Ca2+ buffer inside the sarcoplasmic reticulum. Biochem J 337(1):19–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Szentesi P, Szappanos H, Szegedi C, Gönczi M, Jóna I, Cseri J, Kovács L, Csernoch L (2004) Altered elementary calcium release events and enhanced calcium release by thymol in rat skeletal muscle. Biophys J 86(3):1436–1453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S (2013) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1:CD004816. doi:10.1002/14651858.CD004816.pub5

    PubMed  Google Scholar 

  • Taylor BA, Lorson L, White CM, Thompson PD (2015) A randomized trial of coenzyme Q10 in patients with confirmed Statin Myopathy. Atherosclerosis. 238(2):329–335

    Article  CAS  PubMed  Google Scholar 

  • Tomlinson SS, Mangione KK (2005) Potential adverse effects of statins on muscle. Phys Ther 85:459–465

    PubMed  Google Scholar 

  • Waclawik AJ, Lindal S, Engel AG (1993) Experimental lovastatin myopathy. J Neuropathol Exp Neurol 52(5):542–549

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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).

Author information

Author notes

    Authors and Affiliations

    1. Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, P.O. Box 22, Debrecen, 4012, Hungary

      J. Vincze, Á. Jenes, M. Füzi, J. Almássy, R. Németh, G. Szigeti, B. Dienes, Z. Gaál, P. Szentesi, I. Jóna & L. Csernoch

    2. Department of Preventive Medicine, Faculty of Public Health, University of Debrecen, Debrecen, Hungary

      P. Kertai

    3. Clinical Center, Institute of Medicine, University of Debrecen, Debrecen, Hungary

      G. Paragh

    Authors
    1. J. Vincze
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Á. Jenes
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. M. Füzi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. J. Almássy
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. R. Németh
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. G. Szigeti
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. B. Dienes
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Z. Gaál
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. P. Szentesi
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. I. Jóna
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. P. Kertai
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. G. Paragh
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. L. Csernoch
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to L. Csernoch.

    Additional information

    J. Vincze and Á. Jenes have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Vincze, J., Jenes, Á., Füzi, M. et al. Effects of fluvastatin and coenzyme Q10 on skeletal muscle in normo- and hypercholesterolaemic rats. J Muscle Res Cell Motil 36, 263–274 (2015). https://doi.org/10.1007/s10974-015-9413-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10974-015-9413-5

    Keywords

    Search

    Navigation