title: Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.
abstract: Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.
authors: Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, USA.
authors: Kisuk
authors: K
authors: Min
authors: Oh-Sung
authors: OS
authors: Kwon
authors: Ashley J
authors: AJ
authors: Smuder
authors: Michael P
authors: MP
authors: Wiggs
authors: Kurt J
authors: KJ
authors: Sollanek
authors: Demetra D
authors: DD
authors: Christou
authors: Jeung-Ki
authors: JK
authors: Yoo
authors: Moon-Hyon
authors: MH
authors: Hwang
authors: Hazel H
authors: HH
authors: Szeto
authors: Andreas N
authors: AN
authors: Kavazis
authors: Scott K
authors: SK
authors: Powers
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D004317:Doxorubicin; D002154:Calpain
references: J Clin Invest. 1996 Sep 1;98(5):1253-60
references: 8787689
references: Semin Oncol. 2006 Jun;33(3 Suppl 8):S2-7
references: 16781283
references: J Am Soc Nephrol. 2013 Jul;24(8):1250-61
references: 23813215
references: Am J Physiol Cell Physiol. 2004 Mar;286(3):C565-72
references: 14602577
references: Am J Physiol Cell Physiol. 2006 Mar;290(3):C844-51
references: 16251473
references: J Neurotrauma. 2001 Nov;18(11):1229-40
references: 11721741
references: Free Radic Biol Med. 2010 Oct 15;49(7):1152-60
references: 20600829
references: Eur J Pharmacol. 2011 Nov 30;670(2-3):541-53
references: 21946105
references: Am J Physiol. 1986 Mar;250(3 Pt 1):C474-9
references: 3953809
references: J Appl Physiol (1985). 2011 Apr;110(4):935-42
references: 21310889
references: Crit Care Med. 2012 Jun;40(6):1857-63
references: 22487998
references: J Appl Physiol (1985). 2010 May;108(5):1376-82
references: 20203072
references: J Mol Cell Cardiol. 2006 Sep;41(3):389-405
references: 16879835
references: Cancer Res. 2002 Aug 15;62(16):4592-8
references: 12183413
references: FASEB J. 1994 Aug;8(11):814-22
references: 8070630
references: Cardiovasc Toxicol. 2007;7(2):101-7
references: 17652813
references: Free Radic Biol Med. 2013 Dec;65:988-96
references: 24017970
references: Cancer Res. 1983 Oct;43(10):4543-51
references: 6309369
references: Biochim Biophys Acta. 1986 Sep 25;861(1):83-94
references: 3019400
references: Br J Cancer. 2009 Jan 27;100(2):311-4
references: 19165199
references: Med Res Rev. 2014 Jan;34(1):106-35
references: 23494977
references: J Biol Chem. 2004 Feb 27;279(9):8290-9
references: 14676206
references: J Appl Physiol (1985). 2007 Jun;102(6):2389-97
references: 17289908
references: J Biol Chem. 2004 Aug 20;279(34):35564-72
references: 15208318
references: J Physiol Biochem. 2013 Jun;69(2):177-87
references: 22890792
references: Antioxid Redox Signal. 2011 Nov 1;15(9):2519-28
references: 21457104
references: Cancer Treat Rep. 1978 Jun;62(6):955-61
references: 352510
references: Biophys J. 2009 Feb 18;96(4):1388-98
references: 19217856
references: Br J Pharmacol. 2014 Apr;171(8):2017-28
references: 24134698
references: Cancer Chemother Pharmacol. 2009 Nov;64(6):1105-13
references: 19352663
references: J Biol Chem. 1986 Mar 5;261(7):3060-7
references: 3456345
references: J Biol Chem. 1997 Feb 28;272(9):5828-32
references: 9038198
references: Science. 1977 Jul 8;197(4299):165-7
references: 877547
references: Mitochondrion. 2011 Jan;11(1):22-6
references: 20599629
references: Biochemistry (Mosc). 2008 Dec;73(12):1329-42
references: 19120018
references: Am J Physiol Endocrinol Metab. 2012 Jul 1;303(1):E31-9
references: 22395111
references: J Appl Physiol (1985). 2009 Dec;107(6):1935-42
references: 19779154
references: Longev Healthspan. 2014 May 01;3:6
references: 24860647
references: J Clin Invest. 2014 Feb;124(2):617-30
references: 24382354
references: Curr Opin Clin Nutr Metab Care. 2012 May;15(3):240-5
references: 22466926
references: J Biol Chem. 2003 Dec 26;278(52):52873-80
references: 14561769
references: Free Radic Biol Med. 2008 Jan 15;44(2):169-79
references: 18191753
references: Biochim Biophys Acta. 1997 Oct 24;1361(3):304-12
references: 9375805
references: Mol Cell Biochem. 2000 Apr;207(1-2):77-86
references: 10888230
references: J Appl Physiol (1985). 2011 Nov;111(5):1459-66
references: 21817113
references: Antioxid Redox Signal. 2007 Nov;9(11):1825-36
references: 17854275
references: Biophys Chem. 1990 Apr;35(2-3):247-57
references: 2204444
references: J Clin Invest. 2009 Mar;119(3):573-81
references: 19188683
references: J Biol Chem. 2004 Aug 13;279(33):34682-90
references: 15178689
references: J Clin Invest. 1997 Sep 15;100(6):1501-6
references: 9294117
references: Am J Respir Crit Care Med. 2007 Jan 15;175(2):150-9
references: 17082496
references: Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1515-24
references: 20833957
references: Crit Care Med. 2011 Jul;39(7):1749-59
references: 21460706
references: Cell Biol Toxicol. 2007 Jan;23(1):15-25
references: 17009097
references: Physiol Rev. 2003 Jul;83(3):731-801
references: 12843408
references: FASEB J. 1997 Oct;11(12):931-6
references: 9337145
references: Muscle Nerve. 2011 Jan;43(1):94-102
references: 21171100
references: Cardiovasc Res. 2008 Jul 1;79(1):89-96
references: 18346979
references: Heart Fail Rev. 2012 May;17(3):395-409
references: 21739365