title: Removal of the cardiac troponin I N-terminal extension improves cardiac function in aged mice.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA. biesiadecki.1@osu.edu
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.forename: Kittipong
authors.initials: K
authors.lastname: Tachampa
authors.forename: Chao
authors.initials: C
authors.lastname: Yuan
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
authors.forename: Pieter P
authors.initials: PP
authors.lastname: de Tombe
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: 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*
chemical_list: D019210:Troponin I; D000251:Adenosine Triphosphatases; D002118:Calcium
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