HMG CoA Reductase Inhibitor-Induced Myotoxicity: Pravastatin and Lovastatin Inhibit the Geranylgeranylation of Low-Molecular-Weight Proteins in Neonatal Rat Muscle Cell Culture

Flint, Oliver; Masters, Barbara A.; Gregg, Richard E.; Durham, Stephen K.

doi:10.1006/taap.1997.8174

Cited by 81 publications

(34 citation statements)

References 36 publications

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“…Others have reported that, in vitro, statins inhibit geranylgeranylation (69), and so it is tempting to speculate that this arm of the HMG-CoA reductase biosynthetic pathway is required to maintain muscle function. PGC-1α expression leading to increased mitochondrial mass might then reduce the effect of statins by increasing the pool of mitochondrial CoQ 10 and placing less of a requirement on new (statin-inhibitable) CoQ 10 production.…”

Section: Discussionmentioning

confidence: 99%

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Hanai¹,

Cao²,

Tanksale³

et al. 2007

J. Clin. Invest.

178

218

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Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.

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Section: Discussionmentioning

confidence: 99%

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Hanai¹,

Cao²,

Tanksale³

et al. 2007

J. Clin. Invest.

178

218

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“…It has been suggested that starvation of mevalonate by inhibition of HMG-CoA reductase might lead to reduced supply of ubiquinone, which is required in mitochondrial electron transport. Supplementation of muscle cell cultures with geranylgeraniol (precursor of ubiquinone but not cholesterol) abrogates the in vitro myotoxicity of statins (Flint et al, 1997a). In vitro studies also show that inhibition of cholesterol synthesis alone via inhibition of squalene synthase does not induce myotoxicity (Flint et al, 1997b).…”

Section: Discussionmentioning

confidence: 99%

Statin-Induced Muscle Necrosis in the Rat: Distribution, Development, and Fibre Selectivity

et al. 2005

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Simvastatin and cerivastatin have been used to investigate the development of statin-induced muscle necrosis in the rat. This was similar for both statins and was treatment-duration dependent, only occurring after 10 days had elapsed even if the dose was increased, and still occurring after this time when dosing was terminated earlier as a result of morbidity. It was then widespread and affected all areas of the muscular system. However, even when myotoxicity was severe, particular individual muscles and some types of fibres within affected muscles were spared consistently. Fibre typing of spared muscles and of acutely necrotic fibres within affected muscles indicated a differential fibre sensitivity to statin-induced muscle necrosis. The fibres showed a necrotic response to statin administration that matched their oxidative/glycolytic metabolic nature: Least sensitive → I ↔ IIA ↔ IID ↔ IIB ← most sensitive. Type I and IIB fibres represent metabolic extremes of a continuum of metabolic properties through the fibre types with type I fibres most oxidative in metabolism and type IIB fibres most glycolytic. In addition, in some (nonnecrotic) glycolytic fibres from muscles showing early multifocal single fibre necrosis the only subcellular alterations present in isolation of any other changes were mitochondrial. These changes were characterised by an increased incidence of vacuolation and the formation of myelinoid vesicular bodies that accumulated in the subsarcolemmal areas. These findings suggest an important early involvement of mitochondria in selective glycolytic muscle fibre necrosis following inhibition of the enzyme HMG-CoA reductase.

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“…Fpp and GGpp are substrates for the posttranslational prenylation of proteins (53)(54)(55). Farnesol is a Fpp-derived metabolite that has been shown recently to induce PPARα activity and thereby influence keratinocyte differentiation (56).…”

Section: Discussionmentioning

confidence: 99%

Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I

Martin

Duez²,

Blanquart³

et al. 2001

J. Clin. Invest.

408

261

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Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARα response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARα activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARα in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.

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HMG CoA Reductase Inhibitor-Induced Myotoxicity: Pravastatin and Lovastatin Inhibit the Geranylgeranylation of Low-Molecular-Weight Proteins in Neonatal Rat Muscle Cell Culture

Cited by 81 publications

References 36 publications

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Statin-Induced Muscle Necrosis in the Rat: Distribution, Development, and Fibre Selectivity

Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I

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