title: Carboxyl terminus of Hsp70-interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise.
abstract: The carboxyl terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase/cochaperone critical for the maintenance of cardiac function. Mice lacking CHIP (CHIP-/-) suffer decreased survival, enhanced myocardial injury and increased arrhythmias compared with wild-type controls following challenge with cardiac ischaemia reperfusion injury. Recent evidence implicates a role for CHIP in chaperone-assisted selective autophagy, a process that is associated with exercise-induced cardioprotection. To determine whether CHIP is involved in cardiac autophagy, we challenged CHIP-/- mice with voluntary exercise. CHIP-/- mice respond to exercise with an enhanced autophagic response that is associated with an exaggerated cardiac hypertrophy phenotype. No impairment of function was identified in the CHIP-/- mice by serial echocardiography over the 5 weeks of running, indicating that the cardiac hypertrophy was physiologic not pathologic in nature. It was further determined that CHIP plays a role in inhibiting Akt signalling and autophagy determined by autophagic flux in cardiomyocytes and in the intact heart. Taken together, cardiac CHIP appears to play a role in regulating autophagy during the development of cardiac hypertrophy, possibly by its role in supporting Akt signalling, induced by voluntary running in vivo.
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: Jin-Na
authors.initials: JN
authors.lastname: Min
authors.forename: Shaobin
authors.initials: S
authors.lastname: Wang
authors.forename: Holly
authors.initials: H
authors.lastname: McDonough
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockyer
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Wadosky
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000818:Animals; D001343:Autophagy; D006332:Cardiomegaly / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt
keywords: CHIP; IGF-1 signalling; autophagy; cardiac hypertrophy; heart; ubiquitin ligase
references.citation: Circulation. 2012 Jun 26;125(25):3170-81
references.pmid: 22592897
references.citation: EMBO J. 2008 Jan 23;27(2):433-46
references.pmid: 18200046
references.citation: Hum Mol Genet. 2004 Apr 1;13(7):703-14
references.pmid: 14962978
references.citation: Circ Res. 2003 Aug 22;93(4):292-301
references.pmid: 12933700
references.citation: Eur J Heart Fail. 2010 Apr;12(4):323-30
references.pmid: 20335351
references.citation: Autophagy. 2010 Jul;6(5):600-6
references.pmid: 20431347
references.citation: Nat Med. 2007 May;13(5):619-24
references.pmid: 17450150
references.citation: J Clin Invest. 2005 Mar;115(3):527-37
references.pmid: 15765134
references.citation: Postepy Biochem. 2005;51(1):88-94
references.pmid: 16209346
references.citation: Circulation. 2006 May 2;113(17):2097-104
references.pmid: 16636172
references.citation: Pflugers Arch. 1998 Jun;436(1):26-32
references.pmid: 9560443
references.citation: J Cardiovasc Pharmacol. 2012 Sep;60(3):248-52
references.pmid: 22743635
references.citation: Traffic. 2000 Jul;1(7):570-83
references.pmid: 11208145
references.citation: Autophagy. 2011 Oct;7(10):1259-60
references.pmid: 21677510
references.citation: J Biol Chem. 2007 Jul 27;282(30):21945-52
references.pmid: 17525155
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3622-7
references.pmid: 18292230
references.citation: Novartis Found Symp. 2006;274:118-26; discussion 126-31, 152-5, 272-6
references.pmid: 17019809
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;45(1):97-106
references.pmid: 6142562
references.citation: Circ Res. 2009 Jul 2;105(1):80-8
references.pmid: 19498199
references.citation: Curr Top Dev Biol. 2006;73:205-35
references.pmid: 16782460
references.citation: Curr Biol. 2001 Mar 6;11(5):361-5
references.pmid: 11267874
references.citation: Acta Physiol Hung. 2009 Sep;96(3):267-76
references.pmid: 19706370
references.citation: J Clin Invest. 2007 Mar;117(3):648-58
references.pmid: 17304350
references.citation: J Mol Cell Cardiol. 2011 Oct;51(4):584-93
references.pmid: 21723289
references.citation: Circ Res. 2007 Nov 9;101(10):975-84
references.pmid: 17991891
references.citation: Biochem J. 1999 Jul 15;341 ( Pt 2):233-49
references.pmid: 10393078
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10132-6
references.pmid: 15220483
references.citation: Nat Cell Biol. 2001 Jan;3(1):93-6
references.pmid: 11146632
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2836-42
references.pmid: 15665051
references.citation: J Cardiovasc Transl Res. 2010 Aug;3(4):365-73
references.pmid: 20559777
references.citation: J Biol Chem. 2001 Nov 16;276(46):42938-44
references.pmid: 11557750
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4123-8
references.pmid: 21367693
references.citation: Trends Biochem Sci. 1990 Aug;15(8):305-9
references.pmid: 2204156
references.citation: Cell Death Differ. 2005 Dec;12(12):1613-21
references.pmid: 15947785
references.citation: Aging Cell. 2009 Sep;8(5):607-13
references.pmid: 19678809
references.citation: J Biol Chem. 2004 Feb 6;279(6):4782-93
references.pmid: 14597618
references.citation: J Biol Chem. 2006 Oct 27;281(43):32841-51
references.pmid: 16950770
references.citation: Mol Cell Biol. 2008 Jun;28(12):4018-25
references.pmid: 18411298
references.citation: Cardiol Res Pract. 2011 Mar 06;2011:972807
references.pmid: 21403846
references.citation: Circulation. 2008 May 27;117(21):2743-51
references.pmid: 18490523
references.citation: J Biol Chem. 1988 May 15;263(14):6797-805
references.pmid: 3360807
references.citation: Heart Fail Rev. 2013 Sep;18(5):585-94
references.pmid: 23054219
references.citation: Novartis Found Symp. 2006;274:90-111; discussion 111-7, 152-5, 272-6
references.pmid: 17019808
references.citation: J Am Coll Cardiol. 2002 Oct 2;40(7):1267-74
references.pmid: 12383574
references.citation: Med Sci Sports Exerc. 2006 Mar;38(3):455-62
references.pmid: 16540832
references.citation: J Biol Chem. 2000 Oct 27;275(43):33329-35
references.pmid: 10938088
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: Curr Biol. 2010 Jan 26;20(2):143-8
references.pmid: 20060297
references.citation: Acta Pathol Microbiol Immunol Scand A. 1984 Jul;92(4):195-204
references.pmid: 6208744
references.citation: Cardiovasc Res. 2004 Feb 1;61(2):218-26
references.pmid: 14736538
references.citation: Circ Res. 2011 Jul 8;109(2):151-60
references.pmid: 21617129
references.citation: J Clin Invest. 2007 Jul;117(7):1782-93
references.pmid: 17607355
references.citation: Circ Res. 2001 Jul 6;89(1):84-91
references.pmid: 11440982
references.citation: Hum Mol Genet. 2010 Sep 1;19(17):3440-56
references.pmid: 20570967
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2979-84
references.pmid: 9501201
references.citation: FASEB J. 2001 Oct;15(12):2286-7
references.pmid: 11511528
references.citation: J Cardiovasc Pharmacol. 2012 Aug;60(2):118-24
references.pmid: 22472907
references.citation: Am J Pathol. 1980 Feb;98(2):425-44
references.pmid: 7355988
references.citation: Annu Rev Physiol. 2010;72:45-59
references.pmid: 20148666
references.citation: Circ Res. 2003 Nov 14;93(10):998-1005
references.pmid: 14576194
references.citation: Trends Biochem Sci. 2002 Jul;27(7):368-75
references.pmid: 12114026
references.citation: N Engl J Med. 2008 Mar 27;358(13):1370-80
references.pmid: 18367740
references.citation: Circ Res. 2007 Mar 2;100(4):456-9
references.pmid: 17272810
references.citation: Curr Hypertens Rep. 2009 Dec;11(6):406-11
references.pmid: 19895751
references.citation: Autophagy. 2010 May;6(4):462-72
references.pmid: 20364102
references.citation: Curr Opin Cardiol. 2010 Jul;25(4):329-34
references.pmid: 20535068
references.citation: Nat Cell Biol. 2012 Aug;14(8):786-8
references.pmid: 22854812
references.citation: J Appl Physiol (1985). 2002 Jun;92(6):2245-55
references.pmid: 12015333
references.citation: Heart Fail Rev. 2002 Apr;7(2):115-30
references.pmid: 11988636
references.citation: Pharmazie. 2007 Dec;62(12):925-9
references.pmid: 18214344
references.citation: Am J Pathol. 2011 Mar;178(3):1059-68
references.pmid: 21356358
references.citation: J Cell Sci. 2000 Dec;113 Pt 24:4441-50
references.pmid: 11082038
references.citation: PLoS One. 2011;6(6):e20975
references.pmid: 21687634
references.citation: Am J Physiol Endocrinol Metab. 2011 Feb;300(2):E327-40
references.pmid: 21045173
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R1006-13
references.pmid: 15618348
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S137-48
references.pmid: 19641499
references.citation: Mol Cell Neurosci. 1999 Sep;14(3):180-98
references.pmid: 10576889
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H455-65
references.pmid: 15734890
references.citation: Basic Res Cardiol. 2009 Mar;104(2):189-202
references.pmid: 19242644
references.citation: J Appl Physiol (1985). 2009 Apr;106(4):1367-73
references.pmid: 19036895
references.citation: Mol Cell Biol. 1999 Jun;19(6):4535-45
references.pmid: 10330192
references.citation: Am J Physiol Cell Physiol. 2010 Aug;299(2):C203-10
references.pmid: 20357180
references.citation: Biochem Biophys Res Commun. 2006 Feb 24;340(4):1125-33
references.pmid: 16403436
references.citation: J Hypertens Suppl. 1990 Dec;8(7):S219-24
references.pmid: 1965655
references.citation: Autophagy. 2011 Nov;7(11):1382-3
references.pmid: 21997373
references.citation: J Biol Chem. 2005 Nov 18;280(46):38673-81
references.pmid: 16169850
references.citation: Autophagy. 2012 Sep;8(9):1394-6
references.pmid: 22889942
references.citation: Trends Mol Med. 2007 Jan;13(1):32-8
references.pmid: 17127096
references.citation: Biochem Soc Trans. 2007 Nov;35(Pt 5):1314-6
references.pmid: 17956340
references.citation: Circulation. 2011 Nov 8;124(19):2117-28
references.pmid: 21986281
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9745-50
references.pmid: 18621691
references.citation: J Biol Chem. 2006 Oct 6;281(40):29776-87
references.pmid: 16882669
references.citation: J Cell Physiol. 2008 Feb;214(2):316-21
references.pmid: 17941081
references.citation: J Clin Invest. 2007 Nov;117(11):3211-23
references.pmid: 17965779
references.citation: Nat Cell Biol. 2012 Aug;14(8):829-37
references.pmid: 22820375
references.citation: Circ Res. 2010 Jun 11;106(11):1692-702
references.pmid: 20413784
references.citation: Cell Death Differ. 2007 Sep;14(9):1647-56
references.pmid: 17541427
references.citation: Circulation. 2001 May 15;103(19):2402-7
references.pmid: 11352891
references.citation: J Appl Physiol (1985). 2001 May;90(5):1900-8
references.pmid: 11299284