Document Detail

Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes.
MedLine Citation:
PMID:  22080086     Owner:  NLM     Status:  MEDLINE    
Statins, the widely prescribed cholesterol-lowering drugs for the treatment of cardiovascular disease, cause adverse skeletal muscle side effects ranging from fatigue to fatal rhabdomyolysis. The purpose of this study was to determine the effects of simvastatin on mitochondrial respiration, oxidative stress, and cell death in differentiated primary human skeletal muscle cells (i.e., myotubes). Simvastatin induced a dose-dependent decrease in viability of proliferating and differentiating primary human muscle precursor cells, and a similar dose-dependent effect was noted in differentiated myoblasts and myotubes. Additionally, there were decreases in myotube number and size following 48 h of simvastatin treatment (5 μM). In permeabilized myotubes, maximal ADP-stimulated oxygen consumption, supported by palmitoylcarnitine+malate (PCM, complex I and II substrates) and glutamate+malate (GM, complex I substrates), was 32-37% lower (P<0.05) in simvastatin-treated (5 μM) vs control myotubes, providing evidence of impaired respiration at complex I. Mitochondrial superoxide and hydrogen peroxide generation were significantly greater in the simvastatin-treated human skeletal myotube cultures compared to control. In addition, simvastatin markedly increased protein levels of Bax (proapoptotic, +53%) and Bcl-2 (antiapoptotic, +100%, P<0.05), mitochondrial PTP opening (+44%, P<0.05), and TUNEL-positive nuclei in human skeletal myotubes, demonstrating up-regulation of mitochondrial-mediated myonuclear apoptotic mechanisms. These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis in primary human skeletal myotubes, suggesting that mitochondrial dysfunction may underlie human statin-induced myopathy.
Hyo-Bum Kwak; Anna Thalacker-Mercer; Ethan J Anderson; Chien-Te Lin; Daniel A Kane; Nam-Sihk Lee; Ronald N Cortright; Marcas M Bamman; P Darrell Neufer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-10-25
Journal Detail:
Title:  Free radical biology & medicine     Volume:  52     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-02     Completed Date:  2012-04-17     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  198-207     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Adenosine Diphosphate / pharmacology
Anticholesteremic Agents / adverse effects
Apoptosis / drug effects
Cell Differentiation / drug effects
Cell Respiration / drug effects
Dose-Response Relationship, Drug
Electron Transport Complex I / genetics,  metabolism
Gene Expression / drug effects*
Hydrogen Peroxide / metabolism
Mitochondria / drug effects*,  metabolism
Muscle Fibers, Skeletal / cytology,  drug effects*,  metabolism
Muscular Diseases / chemically induced,  metabolism*,  pathology
Myoblasts / cytology,  drug effects,  metabolism
Oxidative Stress
Oxygen Consumption / drug effects,  physiology
Primary Cell Culture
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Respiratory System Agents / pharmacology
Signal Transduction / drug effects*
Simvastatin / adverse effects*
Superoxides / metabolism
Grant Support
R01 AG017896/AG/NIA NIH HHS; R01 DK073488/DK/NIDDK NIH HHS; R01 DK073488/DK/NIDDK NIH HHS; R01 DK073488-02/DK/NIDDK NIH HHS; R01 DK073488-03/DK/NIDDK NIH HHS; R01 DK074825/DK/NIDDK NIH HHS; R01 DK074825/DK/NIDDK NIH HHS; R01 DK074825-02/DK/NIDDK NIH HHS; R01 DK074825-03/DK/NIDDK NIH HHS; R01 DK075880/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Proto-Oncogene Proteins c-bcl-2; 0/Respiratory System Agents; 11062-77-4/Superoxides; 61D2G4IYVH/Adenosine Diphosphate; AGG2FN16EV/Simvastatin; BBX060AN9V/Hydrogen Peroxide; EC Transport Complex I

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