Effect of simvastatin on cholesterol metabolism in C2C12 myotubes and HepG2 cells, and consequences for statin-induced myopathy

Mullen, Peter; Lüscher, Barbara; Scharnagl, Hubert; Krähenbühl, Stephan; Brecht, Karin

doi:10.1016/j.bcp.2009.12.007

Cited by 74 publications

(71 citation statements)

References 47 publications

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“…It is difficult, however, to explain by this mechanism why statins impair the AKT signaling pathway. A possible explanation may be related to the observations that prenylation is important for the function of small GTPases [12] and that statins can inhibit their prenylation [30]. Rab1, a prenylated small GTPase, has been shown to stimulate AKT phosphorylation [31] and to possibly be involved in statin-associated muscle damage [12,14].…”

Section: Discussionmentioning

confidence: 97%

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

Bonifacio

Sanvee

Bouitbir

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Statins are drugs that lower blood cholesterol levels and reduce cardiovascular morbidity and mortality. They are generally well-tolerated, but myopathy is a potentially severe adverse reaction of these compounds. The mechanisms by which statins induce myotoxicity are not completely understood, but may be related to inhibition of the AKT signaling pathway. The current studies were performed to explore the down-stream effects of the statin-associated inhibition of AKT within the AKT signaling pathway and on myocyte biology and morphology in C2C12 myotubes and in mice in vivo. We exposed C2C12 myotubes to 10 μM or 50 μM simvastatin, atorvastatin or rosuvastatin for 24 h. Simvastatin and atorvastatin inhibited AKT phosphorylation and were cytotoxic starting at 10 μM, whereas similar effects were observed for rosuvastatin at 50 μM. Inhibition of AKT phosphorylation was associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1 and FoxO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of C2C12 myotubes. Furthermore, impaired AKT phosphorylation was associated with activation of caspases and PARP, reflecting induction of apoptosis. Similar findings were detected in skeletal muscle of mice treated orally with 5 mg/kg/day simvastatin for 3 weeks. In conclusion, this study highlights the importance of the AKT/mTOR signaling pathway in statin-induced myotoxicity and reveals potential drug targets for treatment of patients with statin-associated myopathies.

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Section: Discussionmentioning

confidence: 97%

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

Bonifacio

Sanvee

Bouitbir

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…By suppression of mevalonate synthesis, statins could deplete GGPP or FPP to the extent of preventing small GTPases from prenylation. Accumulating evidence suggests that depletion of isoprenoids, particularly GGPP, is critical for statin-induced myopathy (Flint et al, 1997;Sakamoto et al, 2007), whereas depletions of choles-terol and ubiquinone are not responsible (Mullen et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rab1 GTPase and Endoplasmic Reticulum-to-Golgi Trafficking Underlies Statin's Toxicity in Rat Skeletal Myofibers

Sakamoto

Wada²,

Kimura³

2011

J Pharmacol Exp Ther

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HMG-CoA reductase inhibitor statins are used for the treatment of hypercholesterolemia. However, statins have adverse effects on skeletal muscles with unknown mechanism. We have reported previously that fluvastatin induced vacuolation and cell death in rat skeletal myofibers by depleting geranylgeranylpyrophosphate (GGPP) and suppressing small GTPases, particularly Rab (FASEB J 21:4087-4094, 2007). Rab1 is one of the most susceptible Rab isoforms to GGPP depletion and is essential for endoplasmic reticulum (ER)-to-Golgi trafficking. Here, we explored whether Rab1 and ER-to-Golgi vesicle trafficking were affected by statins in cultured single myofibers isolated from flexor digitorum brevis muscles of adult rats. Western blot analysis revealed that Rab1A protein resided predominantly in membrane but not in cytosol in control myofibers, whereas it was opposite in fluvastatin-treated myofibers, indicating that fluvastatin inhibited Rab1A translocation from cytosol to membrane. GGPP supplementation prevented the effect of fluvastatin on Rab1A translocation. Brefeldin A, a specific suppressor of ER-to-Golgi trafficking, induced vacuolation and cell death in myofibers in a manner similar to that of fluvastatin. Although ER-to-Golgi traffic suppression induces unfolded protein response (UPR) and cell death in some cell types, neither fluvastatin nor brefeldin A up-regulated UPR in myofibers. Immunofluorescence study revealed that the distribution of an ER marker, calnexin, was restricted to the region around nucleus with fluvastatin, suggesting the inhibition of ER membrane traffic by fluvastatin. We conclude that suppression of Rab1 GTPase and the subsequent inhibition of ER-to-Golgi traffic are involved in statin-induced skeletal myotoxicity.

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“…Statins have been reported to decrease superoxide production, in part through downregulation of nicotinamide adenine dinucleotide phosphate oxidase activity (8). Statins also are reported to improve mitochondrial function (26,51), although they have deleterious effects in skeletal muscle (19,27,35,36).…”

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confidence: 99%

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

Andres

Hernandez²,

Lee³

et al. 2014

Antioxidants & Redox Signaling

169

124

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Aims: We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection. Results: HL-1 cardiomyocytes exposed to simvastatin for 24 h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q 10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo. Innovation and Conclusion: Acute simvastatin treatment suppresses mTOR signaling and triggers Parkindependent mitophagy, the latter which is required for cardioprotection. Coadministration of CoQ with simvastatin impairs mitophagy and cardioprotection. These results raise the concern that CoQ may interfere with anti-ischemic benefits of statins mediated through stimulation of mitophagy.

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Effect of simvastatin on cholesterol metabolism in C2C12 myotubes and HepG2 cells, and consequences for statin-induced myopathy

Cited by 74 publications

References 47 publications

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity

Inhibition of Rab1 GTPase and Endoplasmic Reticulum-to-Golgi Trafficking Underlies Statin's Toxicity in Rat Skeletal Myofibers

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

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