Possible Mechanisms Underlying Statin-Induced Skeletal Muscle Toxicity in L6 Fibroblasts and in Rats

Itagaki, Mai; Takaguri, Akira; Kano, Seiichiro; Kaneta, Shigeru; Ichihara, Kazuo; Satoh, Kumi

doi:10.1254/jphs.08238fp

Cited by 55 publications

(43 citation statements)

References 19 publications

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“…2). One group using rat immortalized L6 myoblasts reported that the depletion of FPP is critical for myotoxicity (22), but another laboratory using the same cell line suggested that GGPP was the critical isoprenoid (12). In our hands, it was not FPP (3 mM), but GGPP (3 mM) alone, because the addition of GGPP, not FPP, in the presence of fluvastatin completely canceled the toxic effects of statins in skeletal myofibers (15,17).…”

Section: Depletion Of Geranylgeranylpyrophosphate Triggers Statin Myomentioning

confidence: 62%

“…This discrepancy was more prominent in the case of hydrophilic statins. Although 5-mM serum concentration of pravastatin damaged the skeletal muscle in an animal (rat) experiment, this concentration and a concentration even as high as 1 mM did not cause cell death in cultured rat skeletal myofibers (11,12). Therefore, it seemed inappropriate to analyze the adverse effects of statins using cultured myoblasts.…”

Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 99%

“…It had been reported that inhibition of Rho GTPases and Rho-dependent kinase (ROCK) caused apoptotic cell death among proliferative adherent cells (24). L6 skeletal myoblasts were also damaged by statins due to the inactivation of the Rho/ROCK system (12). However, the inhibitors of either Rho or ROCK did not damage myofibers, unlike (in contrast to their effects on) myoblasts (15,17).…”

Section: Inactivation Of Rab Gtpases Reproduced Statin Myotoxicity Inmentioning

confidence: 99%

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Mechanism of Statin-Induced Rhabdomyolysis

Sakamoto

Kimura

2013

J Pharmacol Sci

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Abstract. Statins, a group of drugs used for the treatment of hypercholesterolemia, have adverse effects on skeletal muscle. The symptoms of these effects range from slight myalgia to severe rhabdomyolysis. The number of patients currently taking statins is estimated to be several millions worldwide. However, the mechanism of statins' myotoxic effects is unclear. Statins inhibit biosynthesis of mevalonate, a rate-limiting step of cholesterol synthesis, by inhibiting HMG-CoA reductase. Mevalonate is also an essential precursor for producing isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. These isoprenoids are especially important for anchoring small GTPases to the membrane before they function; e.g., Ras GTPases modulate proliferation and apoptosis, Rho GTPases control cytoskeleton formation, and Rab GTPases are essential for intracellular vesicle trafficking. Inactivation of these small GTPases alters cellular functions. Recently, we successfully reproduced statin-induced myotoxicity in culture dishes using in vitro skeletal muscle systems (e.g., skeletal myotubes and myofibers). This review summarizes our findings that statins induce depletion of isoprenoids and inactivation of small GTPases, especially Rab, which are critical for statin-induced myotoxicity. Although further study is required, our findings may contribute to the prevention and treatment of statins' adverse effects on skeletal muscle and development of safer anti-hypercholesterolemia drugs.

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Section: Depletion Of Geranylgeranylpyrophosphate Triggers Statin Myomentioning

confidence: 62%

Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 99%

Section: Inactivation Of Rab Gtpases Reproduced Statin Myotoxicity Inmentioning

confidence: 99%

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Mechanism of Statin-Induced Rhabdomyolysis

Sakamoto

Kimura

2013

J Pharmacol Sci

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“…Nevertheless, fluvastatin could partially reverse the impairment of both contractile and diastolic functions in a dose-independent manner; however, the middle dose rather than the high dose of fluvastatin was significantly more effective in improving cardiac function in the DM rats. The DM+FH rats suffered severe rhabdomyolysis-toxicity of the skeletal muscle due to RhoA dysfunction following the loss of lipid modification with geranylgeranyl pyrophos phate [23,24] . Consequently, it was reasonable to presume that pain caused by severe rhabdomyolysis may contribute to the negative impact on cardiac function seen in the DM+FH rats.…”

Section: Discussionmentioning

confidence: 99%

Influence of fluvastatin on cardiac function and baroreflex sensitivity in diabetic rats

Xie

Sun

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate whether fluvastatin is able to ameliorate the impaired cardiac function or baroreflex sensitivity (BRS) in rats with type 1 diabetes. Methods: Type 1 diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ) and then administered fluvastatin (1.5, 3.0, and 6.0 mg·kg -1 ·d -1 ) for 30 d. Food and drink intake was recorded every day. Fasting blood glucose (FBG) level, blood lipid level, cardiac function and BRS were measured in diabetic rats after fluvastatin treatment for 30 d. Results: The polydipsia, polyphagia and abnormal biochemical indexes of blood were significantly ameliorated by the the 3.0-and 6.0-mg doses of fluvastatin in STZ-induced diabetic rats. FBG was decreased in diabetic rats after fluvastatin treatment for 30 d. The left ventricular systolic pressure (LVSP) and the maximum rate of change of left ventricular pressure in the isovolumic contraction and relaxation period (±dp/dt max ) were elevated, and left ventricular diastolic pressure (LVEDP) was decreased by fluvastatin. The attenuated heart rate responses to arterial blood pressure (ABP) increase induced by phenylephrine (PE) and ABP decrease induced by sodium nitroprusside (SNP) were reversed by the 3.0-mg dose of fluvastatin. Conclusion: Fluvastatin regulates blood lipid levels and decreases the FBG level in diabetic rats. These responses can protect the diabetic heart from complications by improving cardiac function and BRS.

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“…12 This is highlighted by the findings that supplementation of geranylgeranylpyrophosphate to cultured skeletal myotubes or isolated myofibers treated with statins leads to attenuation of toxicity, 11,13-15 whereas inactivation of a Rab and RhoA induces toxicity. 11,13 Decreased geranylgeranylation of small GT- …”

mentioning

confidence: 99%

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

Knauer

Urquhart

Schwabedissen

et al. 2010

Circulation Research

182

146

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Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. MG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, statins, are highly effective drugs for the treatment of hypercholesterolemia, a major risk factor of cardiovascular disease. Statins inhibit the synthesis of mevalonate, the rate-limiting step in cholesterol biosynthesis. 1,2 Although statins are generally well tolerated, 3 skeletal muscle side effects are commonly reported among those treated. One such side effect, myalgia, which is defined as muscle aches or weakness in the absence of blood creatine kinase elevation, occurs in 5% to 15% of statin-treated patients. 2,4 -8 In rare cases, potentially life-threatening statin-induced rhabdomyolysis may occur, a condition characterized by acute muscle damage, resulting in pronounced elevation in creatine kinase levels and possible renal failure. 9 The pathophysiology of statin-induced myopathy is not completely understood. The leading mechanism suggests a role for cellular depletion of secondary metabolic intermediates of mevalonate in the development of statin-induced myotoxicity. 10 In addition to decreased cholesterol synthesis, HMG-CoA reductase inhibition by statins causes a commensurate reduction in the levels of downstream metabolic products including isoprenoids, dolichol, and ubiquinone (coenzyme Q10). 10 -13 Among these are the isoprenoid secondary metabolic intermediates geranylgeranylpyrophosphate and farnesylpyrophosphate that are involved in protein isoprenylation and activation of small GTPases such as Rho and Rab. The important role for diminished isoprenylation in the mechanism of statin myotoxicity is related to induction of the muscle atrophy-linked protein atrogin-1. 12 This is highlighted by the findings that supplementation of geranylgeranylpyrophosphate to cultured skeletal myotubes or isolated myofibers treated with statins leads to attenuation of toxicity, 11,13-15 whereas inactivation of a Rab and RhoA induces toxicity. 11,13 Decreased geranylgeranylation of small GT-

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Possible Mechanisms Underlying Statin-Induced Skeletal Muscle Toxicity in L6 Fibroblasts and in Rats

Cited by 55 publications

References 19 publications

Mechanism of Statin-Induced Rhabdomyolysis

Mechanism of Statin-Induced Rhabdomyolysis

Influence of fluvastatin on cardiac function and baroreflex sensitivity in diabetic rats

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

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