title: Susceptibility to simvastatin-induced toxicity is partly determined by mitochondrial respiration and phosphorylation state of Akt.
abstract: Statins are widely used to prevent cardiovascular diseases. They are well-tolerated, with side-effects mainly seen in skeletal muscle. How these side-effects are caused is unknown. We compared isolated primary mouse skeletal muscle myocytes, C2C12 myotubes and liver HepG2 cells to detect differences that could uncover why statins are toxic in skeletal muscle but less so in the liver. 10μM simvastatin caused a decrease in mitochondrial respiration in the primary mouse myocytes and C2C12 myotubes, but had no effect in the HepG2 cells. Mitochondrial integrity is maintained by multiple signaling pathways. One of these pathways, Igf-1/Akt signaling, is also heavily implicated in causing statin-induced toxicity by upregulating atrogin-1. We found that phosphorylated Akt was reduced in C2C12 myotubes but not in HepG2 cells. HepG2 mitochondrial respiration became susceptible to simvastatin-treatment after Akt inhibition, and mitochondrial respiration was rescued in Igf-1-treated C2C12 myotubes. These results suggest that disruption of Igf-1/Akt signaling is a causative factor in simvastatin-induced mitochondrial dysfunction in C2C12 myotubes, whereas HepG2 cells are protected by maintaining Igf-1/Akt signaling. We conclude that phosphorylation of Akt is a key indicator of susceptibility to statin-induced toxicity. How statins can disrupt Igf-1/Akt signaling is unknown. Statins reduce geranylgeranylation of small GTPases, such as Rap1. Previous studies implicate Rap1 as a link between cAMP/Epac and Igf-1/Akt signaling. Transient transfection of constitutively active Rap1 into C2C12 myotubes led to a partial rescue of simvastatin-induced inhibition of mitochondrial respiration, providing a novel link between signaling and respiration.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mullen
authors.forename: Anja
authors.initials: A
authors.lastname: Zahno
authors.forename: Peter
authors.initials: P
authors.lastname: Lindinger
authors.forename: Swarna
authors.initials: S
authors.lastname: Maseneni
authors.forename: Andrea
authors.initials: A
authors.lastname: Felser
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.forename: Karin
authors.initials: K
authors.lastname: Brecht
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019069:Cell Respiration / Q000187:drug effects*; D002478:Cells, Cultured; D056945:Hep G2 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D009124:Muscle Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D019821:Simvastatin; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D020827:rap1 GTP-Binding Proteins