It is not uncommon for clinicians to hear from some of their patients that the use of statins or HMG-CoA reductase inhibitors is associated with myopathy.  Statin-associated myopathy can include myalgia (muscle pains or aches) and myositis (muscle breakdown).1,2  In addition, these conditions may or may not be accompanied by elevations in creatine kinase (CK), but when elevated is associated with muscle breakdown.1,2 

Assuming no other risk factors for myopathy are present, how do statins cause myopathy and is it a direct or indirect effect of the statin on the muscle?
Unfortunately, the exact mechanism for statin associated myopathy is not known and there are conflicting reports in the literature regarding histological changes of the myocytes.  One of the proposed mechanisms that has received a lot of attention is a statin-induced reduction of ubiquinone (coenzyme Q10) in myocytes.3-6  Coenzyme Q10 (CoQ10) is known to decrease oxidative stress through its antioxidant effects and participation in mitochondrial respiration (electron transport chain that generates the majority of the cell's ATP during aerobic metabolism).7-10  Early case reports suggested that CoQ10 supplementation alleviated statin-associated myopathy by preventing mitochondrial dysfunction.3-6  

What is the mechanism by which statins decrease CoQ10 levels?
Statins are well known to inhibit the rate limiting step of cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase, which is responsible for converting HMG-CoA to mevalonate.11,12  When a statin is not present, mevalonate would normally proceed through a series of reactions to eventually produce farnesyl pyrophosphate (PP).  Farnesyl PP can then continue down one of three pathways that will produce cholesterol, heme A, or geranylgeranyl PP.  Heme A is important because it used for the prosthetic group in cytochrome aa3 which is also involved in mitochondrial respiration.  The production of geranylgeranyl PP will go on to do several things, one of which is to produce ubiquinone (CoQ10).  Therefore, since statins inhibit mevalonate, it is plausible that they will also prevent the downstream production of ubiquinone thereby decreasing the availability of ubiquinone and heme A needed for the electron transport chain to work effectively to generate ATP.  If the electron transport chain does not function, aerobic metabolism will decrease resulting in the cytoplasmic shunting of pyruvate to lactate (lactic acid) in order to replenish the NAD+ needed generate the net 2 ATP available from glycolysis.12 If the net production of 2 ATP is not sufficient to maintain cellular metabolism, then the myocyte will theoretically suffer resulting in muscle pains/aches and/or cell death.  Cell death would explain elevated CK concentrations in the circulation.  However, while CoQ10 levels are decreased in the serum as a result of statin therapy, the concentration in the muscles do not necessarily decrease and thus the above proposed and commonly discussed mechanism is not the primary contributor of statin-associated myopathy.13-15  

How else might CoQ10 help prevent statin related muscle problems?
As mentioned earlier, CoQ10 appears to decrease oxidative stress, possibly through its antioxidant effects.7-10  The antioxidant effects of CoQ10 are actually found in its chemically unstable form, reduced CoQ10 (H2CoQ10) which is the form most present in human serum.7-10,16  The generation of H2CoQ10 is facilitated by NADPH-CoQ reductase.  Upon generation of H2CoQ10, it directly reduces lipid peroxyl radicals and facilitates the conversion of alpha-tocopherol radicals back to alpha-tocopherol which allows it to exert its antioxidant effects again.17,18  Together these two antioxidant effects of H2CoQ10 can reduce the oxidative stress that may damage mitochondria prior to any effects on mitochondrial electron transport.  Interestingly, statins have been shown to reduce the NADPH-CoQ reductase activity which, again, is responsible for converting CoQ10 to the more potent antioxidant, H2CoQ10.10  In an animal study, CoQ10 supplementation increased NADPH-CoQ activity even in those animals receiving simvastatin.10 

Therefore, it appears that CoQ10 supplementation may possibly confer beneficial effects through various mechanisms in some patients (e.g., patients with pre-existing deficiencies in CoQ10).3-6,19  However, in contrast to the reported benefits, several recent studies have failed to provide a clear answer to this question or to explain the exact beneficial effect that some patients may receive from CoQ10 supplementation.19-21  As a result, the National Lipid Association's Statin Safety Task Force does not recommend the routine use of coenzyme Q10 supplementation at this time.1  While the evidence is conflicting regarding its benefits, the use of CoQ10 supplementation does not appear to result in any major side effects.

References:

1. Thompson PD, Clarkson PM, Rosenson RS et al.  An assessment of statin safety by muscle experts.  Am J Cardiol  2006;97:69C-76C.
2. Law M, Rudnicka AR.  Statin safety: a systemic review.  Am J Cardiol  2006;97:52C-60C.
3. Folkers K, Langsjoen P, Willis R et al.  Lovastatin decreases coenzyme Q levels in humans.  Proc Natl Acad Sci USA  1990;87:8931-4.
4. Walravens PA, Greene C, Frerman FE.  Lovastatin, isoprenes, and myopathy.  Lancet  1989;2:1097-8.
5. Ogasahara S, Engle AG, Frens D, Mack D.  Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy.  Proc Natl Acad Sci USA  1989;86:2379-82.
6. Chariot P, Abadia R, Agnus D et al.  Simvastatin-induced rhabdomyolysis followed by a MELAS syndrome.  Am J Med  1993;94:109-10.
7. Takahashi T, Shitashige M, Okamoto T et al.  A novel ubiquinone reductase activity in rat cytosol.  FEBS Lett  1992;314:331-4.
8. Takashi T, Yamaguchi T, Shitashige M et al.  Reduction of ubiquinone in membrane lipids by rat liver cytosol and its involvement in the cellular defence system against lipid peroxidation.  Biochem J  1995;309:883-90.
9. Kashi T, Takahashi T, Mizobuchi S et al.  Effect of dicumerol, a Nad(P)h: quinine acceptor oxidoreductase 1 (DT-diaphorase) inhibitor on ubiquinone redox cycling in cultured rat hepatocytes.  Free Rad Res  2002;36:413-9.
10. Kettawan A, Takahashi T, Kongkachuichai R et al.  Protective effects of coenzyme q(10) on decreased oxidative stress resistance induced by simvastatin.  J Clin Biochem Nutr  2007;40:194-202.
11. Goldstein JL, Brown MS.  Regulation of the mevalonate pathway.  Nature  1990;343:425-30. 
    
12. Lieberman M, Marks AD.  Chapter 34: Cholesterol absorption, synthesis, metabolism, and fate.  In: Mark's Basic Medical Biochemistry.  A Clinical Approach.  3^rd ed.  Lieberman M, Marks AD eds.  Wolters Kluwer & Lippincott Williams & Wilkins.  Philadelphia, PA.  2009;635-643. 
13. Laaksonen R, Jokelainen K, Sahi T et al.  Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans.  Clin Pharmacol Ther  1995;57:62-6.
14. Laaksonen R, jokelainen K, Laakso J et al.  The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.  Am J Cardiol  1996;77:851-4.
15. Palva 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;78:60-8.
16. Okamoto T, Matsuya T, Fukunaga Y et al.  Human serum ubiquinol-10 levels and relationship to serum lipids.  Int J Vitam Nutr Res  1989;59:288-92.
17. Yamamoto Y, Komuro E, Niki E.  Antioxidant activity of ubiquinol in solution and phosphatidylcholine liposome.  J Nutr Sci Vitaminol  1990;36:505-11.
18. Landi L, Cabrini L, Fiorentini D et al.  The antioxidant activity of ubiquinol-3 in homogenous solution and in liposomes.  Chem Phys Lipids  1992;61:121-30.
19. Caso G, Kelly P, McNurlan MA, Lawson WE.  Effects of coenzyme q10 on myopathic symptoms in patients treated with statins.  Am J Cardiol  2007;99:1409-12.
20. Mabuchi H, Nohara A, Kobayashi J et al.  Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study.  Atherosclerosis  2007;195:e182-9.
21. Young JM, Florkowski CM, Molyneux SL et al.  Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia.  Am J Cardiol  2007;100:1400-3.

Coenzyme Q10, Myositis, Myopathy, Muscle Breakdown, Statins, HMG CoA Reductase Inhibitors and Coenzyme Q10