Some molecular mechanisms of the statin-associated myopathy development

A. L. Zagayko, T. O. Briukhanova

Abstract


Topicality. Statins are the most commonly prescribed lipid-lowering drugs. It is proven that their administration significantly reduces the risk of cardiovascular complications. However, along with high efficiency, they provoke the development of side effects on the muscular system – myopathies and rhabdomyolysis. Mechanisms of myotoxity formation currently remains a controversial issue.

Aim. To summarize the existing literature data concerning the molecular mechanisms underlying the development of myopathy associated with statins treatment.

Results and discussion. According to modern concepts, molecular mechanisms of myopathy and rhabdomyolysis during treatment with statins may be associated with apoptosis of muscle fibers (as a result of violations of proteins post-translational modification); has an autoimmune nature (through its impact on major histocompatibility complex); lesion of ubiquitin-proteasome system; due to deficiency of ubiquinone and carnitine, and decreased synthesis of endogenous cholesterol.

Conclusions. Molecular mechanisms of statin-associated myopathy development are complex and have both idiopathic and genetically nature.


Keywords


statins; atherosclerosis; myopathy; rhabdomyolysis; ubiquinone; apoptosis

References


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Mohassel, P., Mammen, A. L. (2013). The spectrum of statin myopathy. Current Opinion in Rheumatology, 25 (6), 747–752. doi: 10.1097/01.bor.0000434673.85515.89

Harper, C. R., Jacobson, T. A. (2007). The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis. Current Opinion in Lipidology, 18 (4), 401–408. doi: 10.1097/mol.0b013e32825a6773

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Schirris, T. J. J., Renkema, G. H., Ritschel, T., Voermans, N. C., Bilos, A., van Engelen, B. G. M., Russel, F. G. M. (2015). Statin–Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition. Cell Metabolism, 22 (3), 399–407. doi: 10.1016/j.cmet.2015.08.002

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GOST Style Citations


1.         Toth, P. Clinical characterization and molecular mechanisms of statin myopathy / P. Toth, C. Harper, T. Jacobson // Expert Rev. of Cardiovascular Therapy. – 2008. – Vol. 6, Issue 7. – P. 955–969. doi: 10.1586/14779072.6.7.955

2.         Mohassel, P. The spectrum of statin myopathy / P. Mohassel, A. Mammen // Curr. Opinion in Rheumatol. – 2013. – Vol. 25, Issue 6. – P. 747–752. doi: 10.1097/01.bor.0000434673.85515.89

3.         Harper, C. The broad spectrum of statin myopathy : from myalgia to rhabdomyolysis / C. Harper, T. Jacobson // Curr. Opinion in Lipidol. – 2007. – Vol. 18, Issue 4. – P. 401–408. doi: 10.1097/mol.0b013e32825a6773

4.         Statin–induced myopathies / M. Tomaszewski, K. Stępień, J. Tomaszewska,S. Czuczwar// Pharmacol. Reports. – 2011. – Vol. 63, Issue 4. – P. 859–866. doi: 10.1016/s1734–1140(11)70601–6

5.         Molecular basis of statin–associated myopathy / C. Vaklavas, Y. Chatzizisis, A. Ziakas et al. // Atherosclerosis. – 2009. – Vol. 202, Issue 1. – P. 18–28. doi: 10.1016/j.atherosclerosis.2008.05.021

6.         Owczarek, J. Drug–induced myopathies. An overview of the possible mechanisms / J. Owczarek, M. Jasiñska, D. Orszulak–Michalak // Pharmacol. Rep. – 2005. – Vol. 57. – P. 23–34.

7.         Mechanisms and assessment of statin-related muscular adverse effects / D. Moßhammer,E. Schaeffeler, M. Schwab, K. Mörike // British J. of Clin. Pharmacol. – 2014. – Vol. 78, Issue 3. – P. 454–466. doi: 10.1111/bcp.12360

8.         Statin myopathy : the fly in the ointment for the prevention of cardiovascular disease in the 21st century? / H. Keen, J. Krishnarajah, T. Bates, G. Watts // Expert Opinion on Drug Safety. – 2014. – Vol. 13, Issue 9. – P. 1227–1239. doi: 10.1517/14740338.2014.937422

9.         Rosenson, R. Current overview of statin–induced myopathy / R. S. Rosenson // Am. J. of Medicine. – 2004. – Vol. 116, Issue 6. – P. 408–416. doi: 10.1016/j.amjmed.2003.10.033

10.       Phillips, P. Statin myopathy as a metabolic muscle disease / P. Phillips, R. Haas // Expert Review of Cardiovascular Therapy. – 2008. – Vol. 6, Issue 7. – P. 971–978. doi: 10.1586/14779072.6.7.971

11.      Taylor, B. Muscle–related side–effects of statins : from mechanisms to evidence–based solutions / B. Taylor, P. Thompson // Curr. Opinion in Lipidol. – 2015. – Vol. 26, Issue 3. – P. 221–227. doi: 10.1097/mol.0000000000000174

12.       Sirvent, P. New insights into mechanisms of statin–associated myotoxicity / P. Sirvent, J. Mercier, A. Lacampagne // Curr. Opinion in Pharmacol. – 2008. – Vol. 8, Issue 3. – P. 333–338. doi: 10.1016/j.coph.2007.12.010

13.       Statin–associated myopathy : from genetic predisposition to clinical management / M. Vrablik, L. Zlatohlavek, T. Stulc et al. // Physiological Res. – 2014. – Vol. 63. – S327 p.

14.       Mechanisms of statin–induced myalgia assessed by physiogenomic associations / G. Ruaño, A. Windemuth, A. Wu et al. // Atherosclerosis. – 2011. – Vol. 218, Issue 2. – P. 451–456. doi: 10.1016/j.atherosclerosis.2011.07.007

15.       A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy / B. Taylor, L. Lorson, C. White, P. Thompson // Atherosclerosis. – 2015. – Vol. 238, Issue 2. – P. 329–335. doi: 10.1016/j.atherosclerosis.2014.12.016

16.       Apostolopoulou, M. The role of mitochondria in statin-induced myopathy / M. Apostolopoulou, A. Corsini, M. Roden // Eur. J. of Clin. Investigation. – 2015. – Vol. 45, Issue 7. – P. 745–754. doi: 10.1111/eci.12461

17.       The interaction between statins and exercise: mechanisms and strategies to counter the musculoskeletal side effects of this combination therapy / R. Deichmann, C. Lavie, T. Asher et al. // The Ochsner J. – 2015. – Vol. 15. – P. 429–437.

18.       Du Souich, P. Myotoxicity of statins : Mechanism of action / P. du Souich, G. Roederer, R. Dufour // Pharmacol. & Therapeutics. – 2017. doi: 10.1016/j.pharmthera.2017.02.029

19.       Ghatak, A. The genetics of statin–induced myopathy / A. Ghatak, O. Faheem, P. Thompson // Atherosclerosis. – 2010. – Vol. 210, Issue 2. – P. 337–343. doi: 10.1016/j.atherosclerosis.2009.11.033

20.      Needham, M. Statin myotoxicity : a review of genetic susceptibility factors / M. Needham, F. Mastaglia // Neuromuscular Dis. – 2014. – Vol. 24, Issue 1. – P. 4–15. doi: 10.1016/j.nmd.2013.09.011

21.       Statins induce post–translational modification of RyR1 in human and rodent skeletal muscle : a mechanism for myopathy /S. Lotteau, J. Colyer, P. Hopkins, D. Steele // The Physiological Society. – 2016.

22.       Statin–Induced Myopathy is Mediated by Isoprenoid Depletion and is Independent of Serum Cholesterol Levels / J. Lawrence, C. Moyer, M. Ameri et al. // Circulation. – 2014. – Vol. 130. – P. A13907–A13907.

23.       Statin–associated myopathy and the quest for biomarkers : can we effectively predict statin–associated muscle symptoms? / D. Muntean, P. Thompson, A. Catapano et al. // Drug Discovery Today. – 2017. – Vol. 22, Issue 1. – P. 85–96. doi: 10.1016/j.drudis.2016.09.001

24.       Statin–induced myopathy is associated with mitochondrial complex III inhibition / T. Schirris, G. Renkema, T. Ritschel et al. // Cell Metabolism. – 2015. – Vol. 22, Issue 3. – P. 399–407. doi: 10.1016/j.cmet.2015.08.002

25.       Schaefer, J. Statin Myopathy / J. Schaefer,S. Jackson// In Acquired Neuromuscular Disorders. – 2016. – P. 113–122. doi: 10.1007/978–3–319–29514–5_8





DOI: https://doi.org/10.24959/ubphj.17.113

Abbreviated key title: Ukr. bìofarm. ž.

ISSN 2519-8750 (Online), ISSN 2311-715X (Print)