Ectopic catalase expression in mitochondria by adeno-associated virus enhances exercise performance in mice.
Oxidative stress is thought to compromise muscle contractility. However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise. One possible explanation may relate to the inability of the supplemented antioxidants to effectively eliminate excessive free radicals at the site of generation. Here, we tested whether delivering catalase to the mitochondria, a site of free radical production in contracting muscle, could improve treadmill performance in C57Bl/6 mice. Recombinant adeno-associated virus serotype-9 (AV.RSV.MCAT) was generated to express a mitochondria-targeted catalase gene. AV.RSV.MCAT was delivered to newborn C57Bl/6 mouse circulation at the dose of 10(12) vector genome particles per mouse. Three months later, we observed a approximately 2 to 10-fold increase of catalase protein and activity in skeletal muscle and the heart. Subcellular fractionation western blot and double immunofluorescence staining confirmed ectopic catalase expression in the mitochondria. Compared with untreated control mice, absolute running distance and body weight normalized running distance were significantly improved in AV.RSV.MCAT infected mice during exhaustive treadmill running. Interestingly, ex vivo contractility of the extensor digitorum longus muscle was not altered. Taken together, we have demonstrated that forced catalase expression in the mitochondria enhances exercise performance. Our result provides a framework for further elucidating the underlying mechanism. It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease.
Li
Dejia
D
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA.
Lai
Yi
Y
Yue
Yongping
Y
Rabinovitch
Peter S
PS
Hakim
Chady
C
Duan
Dongsheng
D
D000818:Animals; D000831:Animals, Newborn; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000201:enzymology*; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal
D002374:Catalase
Lipids Health Dis. 2004 Jun 22;3:14
15212697
Free Radic Res. 2007 Feb;41(2):182-90
17364944
Free Radic Biol Med. 2005 Sep 1;39(5):651-7
16085183
Aging Cell. 2009 Feb;8(1):73-5
19077044
Cancer Res. 2006 Mar 1;66(5):2497-9
16510562
J Biol Chem. 1991 Nov 15;266(32):22028-34
1657986
Hum Gene Ther. 2008 Aug;19(8):851-6
18666839
Biotechniques. 2002 Sep;33(3):672, 674, 676-8
12238777
J Appl Physiol (1985). 2008 Mar;104(3):853-60
18006866
Ann N Y Acad Sci. 2004 Dec;1031:158-68
15753142
Science. 2005 Jun 24;308(5730):1909-11
15879174
Muscle Nerve. 2007 Dec;36(6):833-41
17696155
Free Radic Biol Med. 2007 Aug 15;43(4):477-503
17640558
Mech Ageing Dev. 2003 Feb;124(2):219-27
12633942
J Nutr Biochem. 2007 Jun;18(6):357-71
17156994
Diabetes. 2004 Sep;53(9):2271-80
15331536
Mech Ageing Dev. 2004 Oct-Nov;125(10-11):811-26
15541775
J Sports Sci. 2004 Jan;22(1):81-94
14971435
Gene Ther. 2007 Nov;14(22):1605-9
17898796
Physiol Rev. 2008 Oct;88(4):1243-76
18923182
Crit Rev Eukaryot Gene Expr. 2008;18(1):81-91
18197787
J Appl Physiol (1985). 2007 Dec;103(6):1917-8
17916668
J Gerontol A Biol Sci Med Sci. 2008 Aug;63(8):813-22
18772469
Proc Natl Acad Sci U S A. 2009 May 26;106(21):8665-70
19433800
Cell. 1986 Feb 14;44(3):451-9
3943133
Mol Ther. 2007 Apr;15(4):750-5
17264855
Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R18-36
16917020
Anal Biochem. 1971 Nov;44(1):301-5
4109029
Toxicology. 2003 Jul 15;189(1-2):41-54
12821281
Circulation. 2009 Jun 2;119(21):2789-97
19451351
Free Radic Biol Med. 2008 Jan 15;44(2):169-79
18191753
Aging Cell. 2006 Apr;5(2):109-17
16626390
Circulation. 2003 Sep 30;108(13):1626-32
12952841
J Appl Physiol (1985). 2007 Apr;102(4):1677-86
17095633
J Biol Chem. 2007 Aug 17;282(33):24407-15
17576767
Mol Ther. 2008 Dec;16(12):1944-52
18827804
Ann N Y Acad Sci. 2002 Apr;959:108-16
11976190
Acta Neuropathol. 1996 Oct;92(4):331-40
8891064
J Gerontol. 1957 Jul;12(3):257-63
13463294
Muscle Nerve. 2007 Apr;35(4):411-29
17266144
Am J Physiol Regul Integr Comp Physiol. 2006 Apr;290(4):R926-34
16339385
J Appl Physiol (1985). 2007 May;102(5):2056-63
17218425
Am J Phys Med Rehabil. 2002 Nov;81(11 Suppl):S175-86
12409822
J Virol. 2004 Jun;78(12):6381-8
15163731
Aging Cell. 2007 Apr;6(2):189-95
17328687
Mol Ther. 2005 Feb;11(2):245-56
15668136
Sports Med. 2005;35(12):1045-62
16336008
J Biol Chem. 1999 Sep 10;274(37):26217-24
10473575
Am J Pathol. 2008 May;172(5):1332-41
18385524
Free Radic Biol Med. 2008 Jan 15;44(2):132-41
18191749
Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2768-76
15319208
Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L978-86
16387755
J Appl Physiol (1985). 2007 Apr;102(4):1664-70
17082364
Nat Protoc. 2007;2(2):287-95
17406588
Cell. 2005 Feb 25;120(4):483-95
15734681
J Clin Invest. 2009 Mar;119(3):573-81
19188683
Methods Enzymol. 1984;105:121-6
6727660
FEBS Lett. 1978 May 1;89(1):126-30
658391