title: Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance.
abstract: OBJECTIVE
  Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9).
  
  
  BACKGROUND
  A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism.
  
  
  METHODS
  Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined.
  
  
  RESULTS
  Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects.
  
  
  CONCLUSIONS
  These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.
authors.affiliation: Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. stelar@sund.ku.dk
authors.forename: Steen
authors.initials: S
authors.lastname: Larsen
authors.forename: Nis
authors.initials: N
authors.lastname: Stride
authors.forename: Martin
authors.initials: M
authors.lastname: Hey-Mogensen
authors.forename: Christina N
authors.initials: CN
authors.lastname: Hansen
authors.forename: Lia E
authors.initials: LE
authors.lastname: Bang
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
authors.forename: Lars B
authors.initials: LB
authors.lastname: Nielsen
authors.forename: Jørn W
authors.initials: JW
authors.lastname: Helge
authors.forename: Flemming
authors.initials: F
authors.lastname: Dela
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D016022:Case-Control Studies; D019069:Cell Respiration / Q000502:physiology; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D018149:Glucose Intolerance / Q000209:etiology*; D005951:Glucose Tolerance Test; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010085:Oxidative Phosphorylation; D019821:Simvastatin / Q000009:adverse effects*; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014451:Ubiquinone; D019821:Simvastatin; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; C024989:coenzyme Q10