title: Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo.
abstract: Simvastatin is effective and well tolerated, with adverse reactions mainly affecting skeletal muscle. Important mechanisms for skeletal muscle toxicity include mitochondrial impairment and increased expression of atrogin-1. The aim was to study the mechanisms of toxicity of simvastatin on H9c2 cells (a rodent cardiomyocyte cell line) and on the heart of male C57BL/6 mice. After, exposure to 10 μmol/L simvastatin for 24 h, H9c2 cells showed impaired oxygen consumption, a reduction in the mitochondrial membrane potential and a decreased activity of several enzyme complexes of the mitochondrial electron transport chain (ETC). The cellular ATP level was also decreased, which was associated with phosphorylation of AMPK, dephosphorylation and nuclear translocation of FoxO3a as well as increased mRNA expression of atrogin-1. Markers of apoptosis were increased in simvastatin-treated H9c2 cells. Treatment of mice with 5 mg/kg/day simvastatin for 21 days was associated with a 5 % drop in heart weight as well as impaired activity of several enzyme complexes of the ETC and increased mRNA expression of atrogin-1 and of markers of apoptosis in cardiac tissue. Cardiomyocytes exposed to simvastatin in vitro or in vivo sustain mitochondrial damage, which causes AMPK activation, dephosphorylation and nuclear transformation of FoxO3a as well as increased expression of atrogin-1. Mitochondrial damage and increased atrogin-1 expression are associated with apoptosis and increased protein breakdown, which may cause myocardial atrophy.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, 4031, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bonifacio
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, 4031, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mullen
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, 4031, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Ileana Scurtu
authors.initials: IS
authors.lastname: Mityko
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Luiz C
authors.initials: LC
authors.lastname: Navegantes
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, 4031, Basel, Switzerland.|Department of Biomedicine, University of Basel, Basel, Switzerland.|Swiss Centre of Applied Human Toxicology, Basel, Switzerland.
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, 4031, Basel, Switzerland. kraehenbuehl@uhbs.ch.|Department of Biomedicine, University of Basel, Basel, Switzerland. kraehenbuehl@uhbs.ch.|Swiss Centre of Applied Human Toxicology, Basel, Switzerland. kraehenbuehl@uhbs.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D019821:Simvastatin / Q000633:toxicity*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D045222:Electron Transport Chain Complex Proteins; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins; D000255:Adenosine Triphosphate; D019821:Simvastatin; C486691:Fbxo32 protein, mouse; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D055372:AMP-Activated Protein Kinases
keywords: Apoptosis; Atrogin-1; FoxO transcription factors; Mitochondrial respiration; Simvastatin