Analysis of biochemical changes in muscular tissue of rats with hypercholesterolemia combined introduction of simvastatin and coenzym Q10

DOI: https://doi.org/10.29296/24999490-2021-05-06

Z.I. Mikashinovich, I.A. Semenets Rostov State Medical University, Nakhichevansky line, 29, Rostov-on-Don, 344022, Russian Federation E-mail: [email protected]

Introduction. Statins are a group of effective lipid – lowering medications. A common side effect of long-term statin use is myopathy. The mechanism of its development is not fully understood at the molecular level, making it difficult to find effective drugs preventing and correcting muscle damage. According to one hypothesis, the pathogenesis of statin myopathy is based on CoQ deficiency. The aim of the study. To analyze metabolic changes in the muscle tissue in rats with essential hypercholesterolemia when simvastatin and coenzyme were co-administered. Methods. 120 male rats were divided into two groups: the first group was kept on a vivarium diet, and the second group was administered essential hypercholesterolemia. Animals of the experimental group were divided into subgroups: 1 – on a diet without drug administration; 2 – simvastatin, 3 – simvastatin and CoQ10. At the end of the experiment, the concentrations of pyruvic acid, lactic acid, and reduced glutathione, the activity of glutathione reductase, glutathione peroxidase, and succinate dehydrogenase and cytochrome oxidase were determined in animal muscles. Results. In the muscles of animals with hypercholesterolemia, the introduction of simvastatin promotes the transition to anaerobic oxidation. The administration of simvastatin to animals with hypercholesterolemia was shown to induce a depression of the glutathione-dependent link of antioxidant protection and inhibition of respiratory chain enzymes at the level of cytochrome oxidase and succinate dehydrogenase. Against the background of coenzyme administration, multidirectional changes in lactate and pyruvate are registered in favor of the growth of the latter. The level of reduced glutathione tends to decrease compared to the group receiving simvastatin. The activity of glutathione reductase has not changed, and glutathione peroxidase corresponds to the indices of rats with hypercholesterolemia. The activity of succinate dehydrogenase and cytochrome oxidase is recorded at the level of control values. Conclusion. Combined administration of simvastatin and coenzyme is effective for optimizing the mitochondrial respiratory chain, which can be recommended for clinical studies to evaluate the effectiveness of including coenzyme Q10 in complex therapy of myopathy.
Keywords: 
statins, myopathy, muscle, ubiquinone, coenzyme Q10

Список литературы: 
  1. Schuster H. The GALAXY Program an update on studies investigating efficacy and tolerability of rosuvastatin for reducing cardiovascular risk. Investigating cardiovascular risk reduction – the Rosuvastatin GALAXY Programme. Expert Rev. Cardiovasc. Ther. 2007; 5: 177–93. DOI:10.1586/14779072.5.2.177.
  2. Sever P.S., Dahlof B., Poulter N.R., Wedel H., Beevers G, Caulfield M., Collins R., Kristinsson A., Mehlsen J., Nieminen M., O’Brien E., Östergren J., ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet. 2003; 361: 1149–58. DOI:10.1016/S0140-6736(03)12948-0.
  3. Dolzhenko M.N., Bazilevich A.Ja., Simagina T.V., Konopljanik L.I. Bezopasnost' statinov: za i protiv. Mistetstvo likuvannja. 2010; 2 (68): 26–34. [Dolzhenko M.N., Bazilevich A.YA., Simagina T.V., Konoplyanik L.I. Bezopasnost’ statinov: za i protiv. Mistectvo likuvannya. 2010; 2 (68): 26–34 (in Russian)].
  4. Evans M, Rees A. Effects of HMG-CoA reductase inhibitors on skeletal muscle: are all statins the same? Drug Saf. 2002; 25 (9): 649–63. DOI: 10.2165/00002018-200225090-00004.
  5. Sewright K.A., Clarkson P.M., Thompson P.D. Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep. 2007; 9 (5): 389–96. DOI: 10.1007/s11883-007-0050-3.
  6. Arora R., Liebo M., Maldonado F. Statin-induced myopathy: the two faces of Janus. J. Cardiovasc Pharmacol Ther. 2006; 11 (2): 105–12. DOI: 10.1177/1074248406288758.
  7. Meador B.M., Huey K.A. Statin-associated myopathy and its exacerbation with exercise. Muscle Nerve. 2010; 42 (4): 469–79. DOI: 10.1002/mus.21817.
  8. Dirks A.J., Jones K.M. Statin-induced apoptosis and skeletal myopathy. Am. J. Physiol. Cell. Physiol. 2006; 291 (6): 1208–12. DOI: 10.1152/ajpcell.00226.2006.
  9. Toth P.P., Harper C.R., Jacobson T.A. Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev Cardiovasc Ther. 2008; 6 (7): 955–69. DOI: 10.1586/14779072.6.7.955.
  10. Caso G., Kelly P., McNurlan M.A., Lawson W.E. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am. J. Cardiol. 2007; 99: 1409–12; DOI: 10.1016/j.amjcard.2006.12.063.
  11. Drapkina O.M., Chernova E.M., Korneeva O.N. Statiny i miopatija: molekuljarnye mehanizmy. Ratsional'naja farmakoterapija v kardiologii. 2012; 8 (3): 469–73. [Drapkina O.M., Chernova E.M., Korneeva O.N. Statiny i miopatiya: molekulyarnye mekhanizmy. Ratsional’naya farmakoterapiya v kardiologii. 2012; 8 (3): 469–73. DOI: 10.20996/1819-6446-2012-8-3-469-473 (in Russian)].
  12. Taylor B.A., Lorson L., White C.M., Thompson P.D. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015; 238: 329–35. DOI: 10.1016/j.atherosclerosis.2014.12.016.
  13. Banach M., Serban C., Sahebkar A., Ursoniu S., Rysz J., Muntner P., Toth P.P., Jones S.R., Rizzo M., Glasser S.P., Lip G.Y., Dragan S., Mikhailidis D.P. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015; 90: 24–34. DOI: 10.1016/j.mayocp.2014.08.021.
  14. Skarlovnik A., Janis M., Lunder M., Turk M., Sabovic M. Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study. Med Sci Monit. 2014; 20: 2183–8. DOI: 10.12659/MSM.890777.
  15. Qu H., Guo M., Chai H., Wang W.T., Gao Z.Y., Shi D.Z. Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials. J. Am. Heart Assoc. 2018; 7: e009835. DOI: 10.1161/jaha.118.009835.
  16. Patent RF na izobretenie №2020111021/16.03.20., Mikashinovich Z.I., Belousova E.S., Semenets I.A., Romashenko A.V., Kantarija A.V. Sposob modelirovanija essentsial'noj giperholesterinemii. Opublikovano: 06.10.2020. Bjul. № 28. Ssylka aktivna na 16.10.2020. [Patent RF na izobretenie №2020111021/16.03.20., Mikashinovich Z.I., Belousova E.S., Semenec I.A., Romashenko A.V., Kantarija A.V. Sposob modelirovanija jessencial’noj giperholesterinemii. Opublikovano: 06.10.2020. Bjul. № 28. Ssylka aktivna na 16.10.2020 (in Russian)].
  17. Spravochnik po laboratornym metodam issledovanij. Pod red. L.A. Danilovoj. Izdatel'skij Dom PITER, 2003. [Spravochnik po laboratornym metodam issledovaniy. Pod red. L.A. Danilovoy. Izdatel’skiy Dom PITER, 2003 (in Russian)].
  18. Mikashinovich Z.I., Letunovskij A.V., Volzhin O.O., Belousova E.S. Biohimicheskie issledovanija sljuny v klinicheskoj praktike. M.: Izdatel'stvo RostGMU (Rostov-na-Donu), 2004. [Mikashinovich Z.I., Letunovskiy A.V., Volzhin O.O., Belousova E.S. Biokhimicheskie issledovaniya slyuny v klinicheskoy praktike. M.: Izdatel’stvo RostGMU (Rostov-na-Donu), 2004 (in Russian)].
  19. Mikashinovich Z.I., Belousova E.S., Vinogradova E.V., Semenets I.A. Fermentativnaja antioksidantnaja zaschita v myshtsah krys pri dlitel'nom vvedenii simvastatina. Meditsinskij vestnik Bashkortostana. 2017; 12.1 (67): 54–7. [Mikashinovich Z.I., Belousova E.S., Vinogradova E.V., Semenets I.A. Enzymatic antioxidant protection in rat muscles after long-term administration of simvastatin. Medicinskij vestnik Bashkortostana. 2017; 12.1 (67): 54–7 (in Russian)].
  20. Kalinina E.V., Chernov N.N., Aleid R., Novichkova M.D., Saprin A.N., Berezov T.T. Sovremennye predstavlenija ob antioksidantnoj roli glutationa i glutationzavisimyh fermentov. Vestnik RAMN. 2010; 3: 46–54. [Kalinina E.V., Chernov N.N., Aleid R., Novichkova M.D., Saprin A.N., Berezov T.T. Modern concepts of the antioxidant role of glutathione and glutathione-dependent enzymes. Vestnik RAMN. 2010; 3: 46–54 (in Russian)].
  21. Lankin V.Z., Tihaze A.K., Belenkov Ju.N. Antioksidanty v kompleksnoj terapii ateroskleroza: pro et contra. Kardiologija. 2004; 2: 70 – 81. [Lankin V.Z., Tihaze A.K., Belenkov Yu.N. Antioxidants in the complex therapy of atherosclerosis: pro et contra. Kardiologiya. 2004; 2: 70–81 (in Russian)].