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Insulin prevents and reverts simvastatin-induced toxicity in C2C12 skeletal muscle cells.

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 3?. 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 ?-chain in the endoplasmic reticulum (ER) and increased cleavage of procaspase-12, indicating ER stress. Insulin reduced the expression of the insulin receptor ?-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.

SUBMITTER: Sanvee GM

PROVIDER: S-EPMC6520350 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Insulin prevents and reverts simvastatin-induced toxicity in C2C12 skeletal muscle cells.

Sanvee Gerda M GM Bouitbir Jamal J Krähenbühl Stephan S

Scientific reports 20190515 1

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 ...[more]

PMID: 31092879

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Project description:Chronic inflammation is fundamental for the induction of insulin resistance in the muscle tissue of vertebrates. Although several miRNAs are thought to be involved in the development of insulin resistance, the role of miRNAs in the association between inflammation and insulin resistance in muscle tissue is poorly understood. Herein, we investigated the aberrant expression of miRNAs by conducting miRNA microarray analysis of TNF-?-treated mouse C2C12 myotubes. We identified two miRNAs that were upregulated and six that were downregulated by a >1.5-fold change compared to normal cells. Among the findings, qRT-PCR analysis confirmed that miR-494 is consistently upregulated by TNF-?-induced inflammation. Overexpression of miR-494 in CHO(IR/IRS1) and C2C12 myoblasts suppressed insulin action by down-regulating phosphorylations of GSK-3?/?, AS160 and p70S6K, downstream of Akt. Moreover, overexpression of miR-494 did not regulate TNF-?-mediated inflammation . Among genes bearing the seed site for miR-494, RT-PCR analysis showed that the expression of Stxbp5, an inhibitor of glucose transport, was downregulated following miR-494 inhibition. In contrast, the expression of PTEN decreased in the cells analyzed, thus showing that both positive and negative regulators of insulin action may be simultaneously controlled by miR-494. To investigate the overall effect of miR-494 on insulin signaling, we performed a PCR array analysis containing 84 genes related to the insulin signaling pathway, and we observed that 25% of genes were downregulated (P<0.05) and 11% were upregulated (P<0.05). These results confirm that miR-494 might contribute to insulin sensitivity by positive and negative regulation of the expression of diverse genes. Of note, PCR array data showed downregulation of Slc2A4, a coding gene for Glut4. Altogether, the present study concludes that the upregulation of miR-494 expression by TNF-?-mediated inflammation exacerbates insulin resistance. Therefore, we suggest that miR-494 could prove an important target for the diagnosis and therapy of inflammation-mediated insulin resistance in muscle.

Dataset Information

Insulin prevents and reverts simvastatin-induced toxicity in C2C12 skeletal muscle cells.

Publications

Insulin prevents and reverts simvastatin-induced toxicity in C2C12 skeletal muscle cells.

Similar Datasets

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