title: Statins Trigger Mitochondrial Reactive Oxygen Species-Induced Apoptosis in Glycolytic Skeletal Muscle.
abstract: OBJECTIVE
  Although statins are the most widely used cholesterol-lowering agents, they are associated with a variety of muscle complaints. The goal of this study was to characterize the effects of statins on the mitochondrial apoptosis pathway induced by mitochondrial oxidative stress in skeletal muscle using human muscle biopsies as well as in vivo and in vitro models.
  
  
  RESULTS
  Statins increased mitochondrial H2O2 production, the Bax/Bcl-2 ratio, and TUNEL staining in deltoid biopsies of patients with statin-associated myopathy. Furthermore, atorvastatin treatment for 2 weeks at 10 mg/kg/day in rats increased H2O2 accumulation and mRNA levels and immunostaining of the Bax/Bcl-2 ratio, as well as TUNEL staining and caspase 3 cleavage in glycolytic (plantaris) skeletal muscle, but not in oxidative (soleus) skeletal muscle, which has a high antioxidative capacity. Atorvastatin also decreased the GSH/GSSG ratio, but only in glycolytic skeletal muscle. Cotreatment with the antioxidant, quercetin, at 25 mg/kg/day abolished these effects in plantaris. An in vitro study with L6 myoblasts directly demonstrated the link between mitochondrial oxidative stress following atorvastatin exposure and activation of the mitochondrial apoptosis signaling pathway.
  
  
  METHODS
  Treatment with atorvastatin is associated with mitochondrial oxidative stress, which activates apoptosis and contributes to myopathy. Glycolytic muscles are more sensitive to atorvastatin than oxidative muscles, which may be due to the higher antioxidative capacity in oxidative muscles.
  
  
  CONCLUSIONS
  There is a link between statin-induced mitochondrial oxidative stress and activation of the mitochondrial apoptosis signaling pathway in glycolytic skeletal muscle, which may be associated with statin-associated myopathy.
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .|2 Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .|3 Swiss Centre for Applied Human Research (SCAHT) , Basel, Switzerland .
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .|2 Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .|4 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital , Basel, Switzerland .
authors.forename: François
authors.initials: F
authors.lastname: Singh
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Charles
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .|2 Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .
authors.forename: Anna-Isabel
authors.initials: AI
authors.lastname: Schlagowski
authors.affiliation: 4 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital , Basel, Switzerland .
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bonifacio
authors.affiliation: 5 Service de Neurologie, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .|2 Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.affiliation: 3 Swiss Centre for Applied Human Research (SCAHT) , Basel, Switzerland .|4 Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital , Basel, Switzerland .
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.affiliation: 1 Fédération de Médecine Translationelle, Faculté de Médecine, Institut de Physiologie, Université de Strasbourg , Strasbourg, France .|2 Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg , Strasbourg, France .
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D057645:Deltoid Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide