Journal Title
Title of Journal: Arch Toxicol
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Abbravation: Archives of Toxicology
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Publisher
Springer Berlin Heidelberg
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Authors: Annalisa Bonifacio Gerda M Sanvee Karin Brecht Denise V Kratschmar Alex Odermatt Jamal Bouitbir Stephan Krähenbühl
Publish Date: 2016/10/12
Volume: 91, Issue: 5, Pages: 2223-2234
Abstract
Statins are generally well tolerated but treatment with these drugs may be associated with myopathy The mechanisms of statinassociated myopathy are not completely understood Statins inhibit AKT phosphorylation by an unclear mechanism whereas insulinlike growth factor IGF1 activates the IGF1/AKT signaling pathway and promotes muscle growth The aims of the study were to investigate mechanisms of impaired AKT phosphorylation by simvastatin and to assess effects of IGF1 on simvastatininduced myotoxicity in C2C12 myotubes C2C12 mouse myotubes were exposed to 10 μM simvastatin and/or 10 ng/mL IGF1 for 18 h Simvastatin inhibited the IGF1/AKT signaling pathway resulting in increased breakdown of myofibrillar proteins impaired protein synthesis and increased apoptosis Simvastatin inhibited AKT S473 phosphorylation indicating reduced activity of mTORC2 In addition simvastatin impaired stimulation of AKT T308 phosphorylation by IGF1 indicating reduced activation of the IGF1R/PI3K pathway by IGF1 Nevertheless simvastatininduced myotoxicity could be at least partially prevented by IGF1 The protective effects of IGF1 were mediated by activation of the IGF1R/AKT signaling cascade Treatment with IGF1 also suppressed muscle atrophy markers restored protein synthesis and inhibited apoptosis These results were confirmed by normalization of myotube morphology and protein content of C2C12 cells exposed to simvastatin and treated with IGF1 In conclusion impaired activity of AKT can be explained by reduced function of mTORC2 and of the IGF1R/PI3K pathway IGF1 can prevent simvastatinassociated cytotoxicity and metabolic effects on C2C12 cells The study gives insight into mechanisms of simvastatinassociated myotoxicity and provides potential targets for therapeutic intervention
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