Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance

TY - JOUR

T1 - Simvastatin effects on skeletal muscle

T2 - relation to decreased mitochondrial function and glucose intolerance

AU - Larsen, Steen

AU - Stride, Nis

AU - Hey-Mogensen, Martin

AU - Hansen, Christina N

AU - Bang, Lia E

AU - Bundgaard, Henning

AU - Nielsen, Lars B

AU - Helge, Jørn W

AU - Dela, Flemming

N1 - Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PY - 2013/1/8

Y1 - 2013/1/8

N2 - Objectives: Glucose tolerance and skeletal muscle coenzyme Q10 (Q10) 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 Q10 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 Q10 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 Q10 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.

AB - Objectives: Glucose tolerance and skeletal muscle coenzyme Q10 (Q10) 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 Q10 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 Q10 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 Q10 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.

KW - Blood Glucose

KW - Case-Control Studies

KW - Cell Respiration

KW - Electron Transport

KW - Electron Transport Complex I

KW - Electron Transport Complex II

KW - Glucose Intolerance

KW - Glucose Tolerance Test

KW - Humans

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors

KW - Insulin Resistance

KW - Male

KW - Middle Aged

KW - Mitochondria, Muscle

KW - Muscle Fibers, Skeletal

KW - Muscle, Skeletal

KW - Oxidative Phosphorylation

KW - Simvastatin

KW - Ubiquinone

U2 - 10.1016/j.jacc.2012.09.036

DO - 10.1016/j.jacc.2012.09.036

M3 - Journal article

C2 - 23287371

SN - 0735-1097

VL - 61

SP - 44

EP - 53

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 1

ER -