Abstract
Simvastatin is an inhibitor of the 3-hydroxy-3-methylglutaryl-CoA reductase used for decreasing low density lipoprotein (LDL)-cholesterol in patients. It is well-tolerated but can cause myopathy. Our aims were to enlarge our knowledge regarding mechanisms and effects of insulin on simvastatin-associated myotoxicity in C2C12 myotubes. Simvastatin (10 µM) reduced membrane integrity and ATP content in myotubes treated for 24 hours, which could be prevented and partially reversed concentration- and time-dependently by insulin. Furthermore, simvastatin impaired the phosphorylation of Akt (Protein Kinase B) mainly at Ser473 and less at Thr308, indicating impaired activity of the mammalian Target of Rapamycin Complex 2 (mTORC2). Impaired activation of Akt increased mRNA expression of the muscle atrophy F-Box (MAFbx), decreased activation of the mammalian Target of Rapamycin Complex 1 (mTORC1) and stimulated apoptosis by impairing the Ser9 phosphorylation of glycogen synthase kinase 3β. Decreased phosphorylation of Akt at both phosphorylation sites and of downstream substrates as well as apoptosis were prevented concentration-dependently by insulin. In addition, simvastatin caused accumulation of the insulin receptor β-chain in the endoplasmic reticulum (ER) and increased cleavage of procaspase-12, indicating ER stress. Insulin reduced the expression of the insulin receptor β-chain but increased procaspase-12 activation in the presence of simvastatin. In conclusion, simvastatin impaired activation of Akt Ser473 most likely as a consequence of reduced activity of mTORC2. Insulin could prevent the effects of simvastatin on the insulin signaling pathway and on apoptosis, but not on the endoplasmic reticulum (ER) stress induction.
Highlights
Statins or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors represent a drug class, which is used widely in patients with cardiovascular diseases in order to lower low density lipoprotein (LDL)-cholesterol[1]
In order to investigate whether insulin could prevent, and reverse the simvastatin-associated membrane toxicity, cells were first exposed to www.nature.com/scientificreports simvastatin and/or 10 or 100 ng/mL insulin. (B) Cellular ATP content in myotubes after 24 hours incubation with simvastatin and/or insulin. (C–F) Cells were first incubated with simvastatin and the two concentrations of insulin were added 3 (C), 6 (D), 8 (E) or 12 (F) hours later
Reduced activation of Akt was associated with increased mRNA expression of MAFBx, reduced activity of mammalian Target of Rapamycin Complex 1 (mTORC1) and induction of apoptosis
Summary
Statins or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors represent a drug class, which is used widely in patients with cardiovascular diseases in order to lower LDL-cholesterol[1]. Statins are considered to be safe, but up to 30% of the patients treated with these drugs can develop signs and/or symptoms of muscle injury[3] Muscle injury in such patients includes elevated activity of serum creatine kinase, which can be associated with symptoms such as weakness or pain. The most important risk factor is increased exposure to statins This is illustrated by a dose-dependency of statin-associated creatine kinase (CK) elevation and symptoms of myopathy[6], by drug interactions increasing the systemic statin concentration[5] and by genetic polymorphisms associated with a decrease in the activity of the organic-anion-transporting polypeptide 1B1 (OATP1B1), which transports statins into hepatocytes[7]. The study shows that insulin cannot only prevent, and restore, simvastatin-associated toxicity on C2C12 myotubes and can prevent impaired function of Akt and associated downstream events
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