Removal of the cardiac troponin I N-terminal extension improves cardiac function in aged mice.
The cardiac troponin I (cTnI) isoform contains a unique N-terminal extension that functions to modulate activation of cardiac myofilaments. During cardiac remodeling restricted proteolysis of cTnI removes this cardiac specific N-terminal modulatory extension to alter myofilament regulation. We have demonstrated expression of the N-terminal-deleted cTnI (cTnI-ND) in the heart decreased the development of the cardiomyopathy like phenotype in a beta-adrenergic-deficient transgenic mouse model. To investigate the potential beneficial effects of cTnI-ND on the development of naturally occurring cardiac dysfunction, we measured the hemodynamic and biochemical effects of cTnI-ND transgenic expression in the aged heart. Echocardiographic measurements demonstrate cTnI-ND transgenic mice exhibit increased systolic and diastolic functions at 16 months of age compared with age-matched controls. This improvement likely results from decreased Ca(2+) sensitivity and increased cross-bridge kinetics as observed in skinned papillary bundles from young transgenic mice prior to the effects of aging. Hearts of cTnI-ND transgenic mice further exhibited decreased beta myosin heavy chain expression compared to age matched non-transgenic mice as well as altered cTnI phosphorylation. Finally, we demonstrated cTnI-ND expressed in the heart is not phosphorylated indicating the cTnI N-terminal is necessary for the higher level phosphorylation of cTnI. Taken together, our data suggest the regulated proteolysis of cTnI during cardiac stress to remove the unique cardiac N-terminal extension functions to improve cardiac contractility at the myofilament level and improve overall cardiac function.
Biesiadecki
Brandon J
BJ
Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA. biesiadecki.1@osu.edu
Tachampa
Kittipong
K
Yuan
Chao
C
Jin
Jian-Ping
JP
de Tombe
Pieter P
PP
Solaro
R John
RJ
D008841:Actin Cytoskeleton / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry; D000375:Aging; D000818:Animals; D002118:Calcium / Q000737:chemistry; D004452:Echocardiography / Q000379:methods; D006321:Heart / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D019076:Transgenes; D019210:Troponin I / Q000737:chemistry*
D019210:Troponin I; D000251:Adenosine Triphosphatases; D002118:Calcium
J Mol Cell Cardiol. 2006 Apr;40(4):465-73
16445938
Eur Heart J. 1995 Jul;16 Suppl F:4-6
8521884
Mol Cell Biochem. 1999 Jan;190(1-2):9-32
10098965
N Engl J Med. 1984 Sep 27;311(13):819-23
6382011
Circ Res. 2007 May 25;100(10):1486-93
17446435
Biochemistry. 2003 Jul 1;42(25):7790-800
12820888
J Mol Biol. 2007 Oct 26;373(3):706-22
17854829
Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2112-9
15994854
Biochemistry. 2001 May 22;40(20):5992-6001
11352734
Heart Fail Rev. 2007 Mar;12(1):66-86
17387610
J Clin Invest. 2003 Sep;112(5):768-75
12952925
Circulation. 2000 Feb 8;101(5):558-69
10662755
Biochemistry. 1997 Jun 3;36(22):6754-61
9184157
Circ Res. 2005 Nov 25;97(11):1156-63
16224063
J Biol Chem. 2009 Jan 16;284(3):1583-92
18945669
J Biol Chem. 2008 Nov 28;283(48):33384-93
18815135
Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H647-56
18552161
J Biol Chem. 2001 May 11;276(19):15753-60
11278823
Circ Res. 1994 Mar;74(3):542-9
8118962
Circ Res. 1995 May;76(5):734-41
7728989
J Biol Chem. 2002 Nov 1;277(44):41795-801
12207022
J Mol Cell Cardiol. 1995 Jul;27(7):1383-91
7473784
J Biol Chem. 1997 Apr 18;272(16):10529-37
9099697
Nature. 1976 Aug 12;262(5569):615-7
958429
J Biol Chem. 2005 Feb 25;280(8):6602-9
15611140
FEBS Lett. 1999 Jun 18;453(1-2):107-12
10403385
FASEB J. 2008 Apr;22(4):1246-57
17984178
J Mol Evol. 2009 May;68(5):448-60
19365646
J Mol Cell Cardiol. 2005 Jan;38(1):119-25
15623428
Circulation. 2005 Apr 12;111(14):1738-46
15809371
J Biol Chem. 2004 Apr 2;279(14):13825-32
14736877
Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2480-8
18390820
J Gerontol A Biol Sci Med Sci. 2007 Dec;62(12):1319-25
18166681
J Biol Chem. 2008 May 30;283(22):15114-21
18378675
Proteomics. 2006 Jul;6(14):4176-86
16791825
J Mol Cell Cardiol. 2007 Jan;42(1):247-59
17081561
Circ Res. 2001 May 25;88(10):1059-65
11375276
J Biol Chem. 2009 Feb 20;284(8):5097-106
19106098
Hybridoma. 1990 Dec;9(6):597-608
1706314
Circ Res. 2007 Jul 20;101(2):205-14
17556658