Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone

Johnson, Timothy E.; Zhang, Xiaohua Douglas; Bleicher, Kimberly B.; Dysart, Gary; Loughlin, Amy F; Schaefer, William H.; Umbenhauer, Diane R.

doi:10.1016/j.taap.2004.04.010

Cited by 121 publications

(109 citation statements)

References 53 publications

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“…The results of this study revealed that cerivastatin, which was the most potent inhibitor of cholesterol biosynthesis in HSkMCs, lowered cellular cholesterol, ubiquinone and protein levels strongly, and showed the most potent cytotoxic activity in cells. It has been suggested that statin-induced apoptosis in human myotube cultures similar to our cell culture system is related to the inhibition of HMG-CoA reductase and in part to the inhibition of protein geranylgeranylation 28) . At present, it seemed that the potency of cytotoxicity caused by statin treatment of HSkMCs was mainly correlated with the inhibitory activities of statins toward cholesterol biosynthesis, namely inhibitory activities toward mevalonate biosynthesis followed by the reduction of downstream metabolites in the pathway.…”

Section: Discussionmentioning

confidence: 63%

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

Yamazaki¹,

Suzuki²,

Aoki³

et al. 2006

J Atheroscler Thromb

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Although statins are prescribed as relatively safe and effective drugs for hypercholesterolemic patients, it has been reported that a significant side effect, myopathy, occurs infrequently during medication. Moreover, because statins decrease cardiac ubiquinone levels, the risk of cardiac dysfunction has been suggested. This study sought to evaluate and compare the cytotoxicity of statins (cerivastatin, pitavastatin, fluvastatin, simvastatin, atorvastatin and pravastatin) in cultured human skeletal muscle cells (HSkMCs) and the effects on ubiquinone levels in statin-treated rat skeletal muscle and heart. Cerivastatin, the most potent inhibitor of HMG-CoA reductase, showed the strongest cytotoxicity (over 10-fold) among the statins examined, while the effects of the others were in a similar range. In rat experiments, neither pitavastatin nor cerivastatin decreased ubiquinone levels in skeletal muscle, but both dose-dependently lowered ubiquinone levels in the heart. As the rates of reduction by pitavastatin (9.6% at 30 mg/kg) and cerivastatin (9.7% at 0.3 mg/kg) were almost equal, it was estimated that cerivastatin reduced ubiquinone levels in the rat heart approximately 100-fold more strongly than pitavastatin, based on the effective doses. We found that cerivastatin showed the most potent cytotoxicity in HSkMCs and strongly lowered ubiquinone levels in the rat heart. J Atheroscler Thromb, 2006; 13:295-307.

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Section: Discussionmentioning

confidence: 63%

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

Yamazaki¹,

Suzuki²,

Aoki³

et al. 2006

J Atheroscler Thromb

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“…Sacher et al (40) show that Bax translocates to the mitochondria in response to statin treatment, which may lead to the release of cytochrome c and activation of the mitochondrial-mediated apoptotic signaling pathway. Addition of mevalonate prevents statin-induced apoptosis and caspase-3 activation (19,40). These results suggest that the depletion of downstream products of mevalonate synthesis induces apoptosis of skeletal muscle cells in a mitochondrial-mediated manner in vitro.…”

Section: Statin-induced Apoptosismentioning

confidence: 65%

“…Similar to the apoptosis-inducing effects of statins on many cell types, statins have also been shown to induce apoptosis in skeletal myocytes in vitro. It has recently been shown that various statins can induce apoptosis in skeletal myoblasts, myotubes, and in differentiated primary human skeletal muscle cells, most often in a concentration-dependent manner (19,30,32,40). The data support that statin-induced apoptosis in skeletal muscle cells may be mitochondrial-mediated as shown by an increase in active caspase-9 and caspase-3 (19,40).…”

Section: Statin-induced Apoptosismentioning

confidence: 72%

“…contributing factor causing myopathy, the most common side effect experienced by statin users (19,30,32,40).…”

Section: Statin-induced Apoptosismentioning

confidence: 99%

“…It has recently been shown that various statins can induce apoptosis in skeletal myoblasts, myotubes, and in differentiated primary human skeletal muscle cells, most often in a concentration-dependent manner (19,30,32,40). The data support that statin-induced apoptosis in skeletal muscle cells may be mitochondrial-mediated as shown by an increase in active caspase-9 and caspase-3 (19,40). Sacher et al (40) show that Bax translocates to the mitochondria in response to statin treatment, which may lead to the release of cytochrome c and activation of the mitochondrial-mediated apoptotic signaling pathway.…”

Section: Statin-induced Apoptosismentioning

confidence: 99%

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Statin-induced apoptosis and skeletal myopathy

Dirks¹,

Jones²

2006

American Journal of Physiology-Cell Physiology

208

164

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Muscle Coenzyme Q10 Level in Statin-Related Myopathy

et al. 2005

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Background: Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle-related complaints. Coenzyme Q 10 (CoQ 10 ), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ 10 concentration may have a role in the pathogenesis of statin drug-related myopathy.Objectives: To measure the CoQ 10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug-related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) assay.Design: An open-labeled study of CoQ 10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy.Setting: Neuromuscular centers at 2 academic tertiary care hospitals.Results: Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ 10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients. Conclusion:These data suggest that statin drug-related myopathy is associated with a mild decrease in muscle CoQ 10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.

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Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinone

Cited by 121 publications

References 53 publications

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

Influence of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors on Ubiquinone Levels in Rat Skeletal Muscle and Heart: Relationship to Cytotoxicity and Inhibitory Activity for Cholesterol Synthesis in Human Skeletal Muscle Cells

Statin-induced apoptosis and skeletal myopathy

Muscle Coenzyme Q10 Level in Statin-Related Myopathy

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