Removal of the Cardiac Troponin I N-terminal Extension Improves Cardiac Function in Aged Mice |
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Authors: | Brandon J. Biesiadecki Kittipong Tachampa Chao Yuan Jian-Ping Jin Pieter P. de Tombe R. John Solaro |
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Affiliation: | From the §Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612.;the ‡Department of Physiology and Cell Biology and The Davis Heart and Lung Research Institute, College of Medicine, Ohio State University, Columbus, Ohio 43210, and ;the ¶Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan 48201 |
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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 β-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 Ca2+ 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 β 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. |
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Keywords: | Aging Cardiac Muscle Heart Post-translational Modification Protein Phosphorylation Cardiac Function Skinned Fibers Troponin I |
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