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Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy.

Title: Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy.
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Name(s): Dweck, David, author
Sanchez-Gonzalez, Marcos A, author
Chang, Audrey N, author
Dulce, Raul A, author
Badger, Crystal-Dawn, author
Koutnik, Andrew P, author
Ruiz, Edda L, author
Griffin, Brittany, author
Liang, Jingsheng, author
Kabbaj, Mohamed, author
Fincham, Frank D, author
Hare, Joshua M, author
Overton, J Michael, author
Pinto, Jose R, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2014-08-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca(2+) decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca(2+)-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca(2+) transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca(2+) content. This abnormal Ca(2+) handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na(+)-Ca(2+) exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.
Identifier: FSU_pmch_24973218 (IID), 10.1074/jbc.M114.561472 (DOI), PMC4132808 (PMCID), 24973218 (RID), 24973218 (EID), M114.561472 (PII)
Keywords: Calcium, Cardiac Hypertrophy, Cardiac Muscle, Cardiac Troponin I, Heart Rate Variability, Hypertrophic Cardiomyopathy, Knock-in Mice, Mouse, R21C, Troponin
Grant Number: HL103840, R01 HL094849, 5R01 HL094849, K99 HL103840, R00 HL103840
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132808.
Subject(s): Animals
Calcium Signaling
Cardiomyopathy, Hypertrophic/genetics
Cardiomyopathy, Hypertrophic/metabolism
Cyclic AMP-Dependent Protein Kinases/genetics
Cyclic AMP-Dependent Protein Kinases/metabolism
Diastole
Disease Models, Animal
Male
Mice
Mice, Transgenic
Myocytes, Cardiac/metabolism
Myocytes, Cardiac/pathology
Phosphorylation/physiology
Sarcoplasmic Reticulum/genetics
Sarcoplasmic Reticulum/metabolism
Troponin I/genetics
Troponin I/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_24973218
Owner Institution: FSU
Is Part Of: The Journal of biological chemistry.
1083-351X
Issue: iss. 33, vol. 289

Choose the citation style.
Dweck, D., Sanchez-Gonzalez, M. A., Chang, A. N., Dulce, R. A., Badger, C. -D., Koutnik, A. P., … Pinto, J. R. (2014). Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy. The Journal Of Biological Chemistry. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_24973218