title: Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes.
abstract: 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.
authors.affiliation: Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Hyo-Bum
authors.initials: HB
authors.lastname: Kwak
authors.forename: Anna
authors.initials: A
authors.lastname: Thalacker-Mercer
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Anderson
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lin
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kane
authors.forename: Nam-Sihk
authors.initials: NS
authors.lastname: Lee
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cortright
authors.forename: Marcas M
authors.initials: MM
authors.lastname: Bamman
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019141:Respiratory System Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000009:adverse effects*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D019141:Respiratory System Agents; D013481:Superoxides; D000244:Adenosine Diphosphate; D019821:Simvastatin; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I
references.citation: JAMA. 2003 Apr 2;289(13):1681-90
references.pmid: 12672737
references.citation: Circulation. 2004 Jul 13;110(2):227-39
references.pmid: 15249516
references.citation: Biochem Biophys Res Commun. 2007 Jun 22;358(1):203-8
references.pmid: 17475217
references.citation: Nature. 2000 Oct 12;407(6805):770-6
references.pmid: 11048727
references.citation: Biochem Pharmacol. 1996 Nov 8;52(9):1387-92
references.pmid: 8937448
references.citation: Atherosclerosis. 2011 Mar;215(1):1-8
references.pmid: 21130454
references.citation: Cell Mol Life Sci. 2006 Oct;63(19-20):2415-25
references.pmid: 17013560
references.citation: Br J Clin Pharmacol. 2004 Apr;57(4):525-8
references.pmid: 15025753
references.citation: FASEB J. 2001 Feb;15(2):322-32
references.pmid: 11156948
references.citation: Curr Atheroscler Rep. 2007 Nov;9(5):389-96
references.pmid: 18001622
references.citation: Ann Intern Med. 2002 Oct 1;137(7):581-5
references.pmid: 12353945
references.citation: J Pharmacol Exp Ther. 2005 Sep;314(3):1032-41
references.pmid: 15914674
references.citation: Atherosclerosis. 2009 Jan;202(1):18-28
references.pmid: 18585718
references.citation: Mol Cell Biochem. 2004 Jan-Feb;256-257(1-2):141-55
references.pmid: 14977177
references.citation: Biochim Biophys Acta. 1996 Apr 12;1315(3):217-22
references.pmid: 8611662
references.citation: Free Radic Biol Med. 1999 Sep;27(5-6):612-6
references.pmid: 10490282
references.citation: Curr Opin Lipidol. 2008 Dec;19(6):553-7
references.pmid: 18957876
references.citation: Curr Opin Pharmacol. 2008 Jun;8(3):333-8
references.pmid: 18243052
references.citation: Free Radic Biol Med. 2003 Jul 1;35(1):9-16
references.pmid: 12826251
references.citation: Am J Physiol Cell Physiol. 2006 Dec;291(6):C1208-12
references.pmid: 16885396
references.citation: Pharmacoepidemiol Drug Saf. 2004 Jul;13(7):417-26
references.pmid: 15269925
references.citation: Biochem Pharmacol. 2006 Apr 28;71(9):1324-30
references.pmid: 16540096
references.citation: Toxicology. 2006 Feb 15;219(1-3):124-32
references.pmid: 16343726
references.citation: Pharmacol Res. 2007 Dec;56(6):503-8
references.pmid: 17959387
references.citation: Int J Pharm. 2007 Aug 16;341(1-2):181-8
references.pmid: 17553641
references.citation: Life Sci. 2009 Mar 27;84(13-14):468-81
references.pmid: 19302811
references.citation: Diabetes. 2005 Jul;54(7):2179-87
references.pmid: 15983220
references.citation: Toxicol Appl Pharmacol. 2004 Nov 1;200(3):237-50
references.pmid: 15504460
references.citation: Exp Gerontol. 2004 Sep;39(9):1391-400
references.pmid: 15489062
references.citation: Clin Pharmacol Ther. 2005 Jul;78(1):60-8
references.pmid: 16003294
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Feb;288(2):R337-44
references.pmid: 15637170
references.citation: Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7
references.pmid: 15198967
references.citation: Clin Ther. 2007 Feb;29(2):253-60
references.pmid: 17472818
references.citation: Am J Physiol Heart Circ Physiol. 2009 Sep;297(3):H1069-77
references.pmid: 19617406
references.citation: Br J Clin Pharmacol. 1996 Sep;42(3):333-7
references.pmid: 8877024
references.citation: Curr Opin Rheumatol. 2007 Jan;19(1):67-73
references.pmid: 17143099
references.citation: J Biol Chem. 1998 May 15;273(20):12662-8
references.pmid: 9575229
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Jun;288(6):R1423-31
references.pmid: 15886351
references.citation: Pharmacol Rep. 2007 Sep-Oct;59(5):483-99
references.pmid: 18048949
references.citation: J Mol Cell Cardiol. 2009 Jun;46(6):989-97
references.pmid: 19318235
references.citation: Metabolism. 1997 Oct;46(10):1206-10
references.pmid: 9322808
references.citation: Biochem Biophys Res Commun. 2005 Apr 15;329(3):1067-75
references.pmid: 15752763
references.citation: Med Sci Sports Exerc. 1982;14(1):101-2
references.pmid: 7070249
references.citation: Circ Res. 1998 Sep 7;83(5):490-500
references.pmid: 9734471
references.citation: Br J Pharmacol. 2006 Dec;149(7):909-19
references.pmid: 17031388
references.citation: J Clin Invest. 2009 Mar;119(3):573-81
references.pmid: 19188683
references.citation: J Am Coll Cardiol. 2007 Jun 12;49(23):2231-7
references.pmid: 17560286
references.citation: Semin Vasc Med. 2004 Nov;4(4):347-56
references.pmid: 15861311
references.citation: Toxicol Pathol. 2005;33(2):246-57
references.pmid: 15902968
references.citation: Epidemiology. 2001 Sep;12(5):565-9
references.pmid: 11505177
references.citation: Biochem Biophys Res Commun. 2005 Dec 23;338(3):1426-34
references.pmid: 16271704
references.citation: N Engl J Med. 2004 Apr 8;350(15):1495-504
references.pmid: 15007110