Atherosclerosis
Volume 202, Issue 1 , Pages 18-28 , January 2009

Molecular basis of statin-associated myopathy

  • Christos Vaklavas

      Affiliations

    • Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
  • ,
  • Yiannis S. Chatzizisis

      Affiliations

    • Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 617 525 7745; fax: +1 617 734 1874.
  • ,
  • Anthony Ziakas

      Affiliations

    • 1st Cardiology Department, AHEPA University Hospital, Aristotle University Medical School, Thessaloniki, Greece
  • ,
  • Chrysanthos Zamboulis

      Affiliations

    • 2nd Propedeutic Department of Internal Medicine, Hippokrateion University Hospital, Aristotle University Medical School, Thessaloniki, Greece
  • ,
  • George D. Giannoglou

      Affiliations

    • 1st Cardiology Department, AHEPA University Hospital, Aristotle University Medical School, Thessaloniki, Greece

Received 24 December 2007 ,Revised 13 May 2008 ,Accepted 13 May 2008.

References 

  1. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160–1164
  2. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–430
  3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–1504
  4. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289(13):1681–1690
  5. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke. 2002;33(9):2337–2341
  6. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Int Med. 2007;18(2):90–100
  7. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97(8A):52C–60C
  8. Rosenson RS. Current overview of statin-induced myopathy. Am J Med. 2004;116(6):408–416
  9. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–559
  10. Mukhtar RY, Reckless JP. Statin-induced myositis: a commonly encountered or rare side effect?. Curr Opin Lipidol. 2005;16(6):640–647
  11. Arora R, Liebo M, Maldonado F. Statin-induced myopathy: the two faces of Janus. J Cardiovasc Pharmacol Ther. 2006;11(2):105–112
  12. Antons KA, Williams CD, Baker SK, Phillips PS. Clinical perspectives of statin-induced rhabdomyolysis. Am J Med. 2006;119(5):400–409
  13. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998;19(1):26–37
  14. Nakahara K, Kuriyama M, Sonoda Y, et al. Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol Appl Pharmacol. 1998;152(1):99–106
  15. Reijneveld JC, Koot RW, Bredman JJ, Joles JA, Bar PR. Differential effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on the development of myopathy in young rats. Pediatr Res. 1996;39(6):1028–1035
  16. Masters BA, Palmoski MJ, Flint OP, Gregg RE, Wang-Iverson D, Durham SK. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol. 1995;131(1):163–174
  17. Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol. 1995;27(10):2397–2402
  18. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117–125
  19. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30(11):1280–1287
  20. Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30(5):505–512
  21. Owczarek J, Jasinska M, Orszulak-Michalak D. Drug-induced myopathies. An overview of the possible mechanisms. Pharmacol Rep. 2005;57(1):23–34
  22. McTaggart SJ. Isoprenylated proteins. Cell Mol Life Sci. 2006;63(3):255–267
  23. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6(5):358–370
  24. Grosshans BL, Ortiz D, Novick P. Rabs and their effectors: achieving specificity in membrane traffic. Proc Natl Acad Sci USA. 2006;103(32):11821–11827
  25. Calero M, Chen CZ, Zhu W, et al. Dual prenylation is required for Rab protein localization and function. Mol Biol Cell. 2003;14(5):1852–1867
  26. Gomes AQ, Ali BR, Ramalho JS, et al. Membrane targeting of Rab GTPases is influenced by the prenylation motif. Mol Biol Cell. 2003;14(5):1882–1899
  27. Ostlund C, Worman HJ. Nuclear envelope proteins and neuromuscular diseases. Muscle Nerve. 2003;27(4):393–406
  28. Moustafa ME, Carlson BA, El-Saadani MA, et al. Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Mol Cell Biol. 2001;21(11):3840–3852
  29. Warner GJ, Berry MJ, Moustafa ME, Carlson BA, Hatfield DL, Faust JR. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine. J Biol Chem. 2000;275(36):28110–28119
  30. Moghadasian MH. Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci. 1999;65(13):1329–1337
  31. Flint OP, Masters BA, Gregg RE, Durham SK. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol. 1997;145(1):91–98
  32. Nishimoto T, Tozawa R, Amano Y, Wada T, Imura Y, Sugiyama Y. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes. Biochem Pharmacol. 2003;66(11):2133–2139
  33. Matzno S, Yamauchi T, Gohda M, et al. Inhibition of cholesterol biosynthesis by squalene epoxidase inhibitor avoids apoptotic cell death in L6 myoblasts. J Lipid Res. 1997;38(8):1639–1648
  34. Morikawa S, Murakami T, Yamazaki H, et al. Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb. 2005;12(3):121–131
  35. Matzno S, Yasuda S, Juman S, et al. Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. J Pharm Pharmacol. 2005;57(11):1475–1484
  36. Sakamoto K, Honda T, Yokoya S, Waguri S, Kimura J. Rab-small GTPases are involved in fluvastatin and pravastatin-induced vacuolation in rat skeletal myofibers. FASEB J. 2007;21(14):4087–4094
  37. Beck LA, Hosick TJ, Sinensky M. Isoprenylation is required for the processing of the lamin A precursor. J Cell Biol. 1990;110(5):1489–1499
  38. Lutz RJ, Trujillo MA, Denham KS, Wenger L, Sinensky M. Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina. Proc Natl Acad Sci USA. 1992;89(7):3000–3004
  39. Sinensky M, Beck LA, Leonard S, Evans R. Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis. J Biol Chem. 1990;265(32):19937–19941
  40. Lammerding J, Schulze PC, Takahashi T, et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest. 2004;113(3):370–378
  41. Nikolova V, Leimena C, McMahon AC, et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J Clin Invest. 2004;113(3):357–369
  42. Siddals KW, Marshman E, Westwood M, Gibson JM. Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways. J Biol Chem. 2004;279(37):38353–38359
  43. Baker SK. Molecular clues into the pathogenesis of statin-mediated muscle toxicity. Muscle Nerve. 2005;31(5):572–580
  44. Martin-Rendon E, Blake DJ. Protein glycosylation in disease: new insights into the congenital muscular dystrophies. Trends Pharmacol Sci. 2003;24(4):178–183
  45. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49(23):2231–2237
  46. Chatzizisis YS, Vaklavas C, Giannoglou GD. Coenzyme q10 depletion: etiopathogenic or predisposing factor in statin associated myopathy?. Am J Cardiol. 2008;101(7):1071
  47. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99(10):1409–1412
  48. Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol. 2007;100(9):1400–1403
  49. Paiva H, Thelen KM, Van Coster R, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. 2005;78(1):60–68
  50. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(8A):89C–94C
  51. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370(9601):1781–1790
  52. Charlton-Menys V, Durrington PN. Squalene synthase inhibitors: clinical pharmacology and cholesterol-lowering potential. Drugs. 2007;67(1):11–16
  53. Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract. 2005;59(2):239–252

PII: S0021-9150(08)00356-0

doi: 10.1016/j.atherosclerosis.2008.05.021

Atherosclerosis
Volume 202, Issue 1 , Pages 18-28 , January 2009