TY - JOUR
T1 - Effect of exercise on passive myocardial stiffness in mice with diastolic dysfunction
AU - Slater, Rebecca E.
AU - Strom, Joshua G.
AU - Granzier, Henk
N1 - Funding Information:
We are grateful to our current and former lab members (in particular Chandra Saripalli, Luann Wyly, and Javier Perez) who contributed to this work and to the University of Arizona Genetic Engineering of Mouse Models (GEMM) and Mouse Phenotyping Core Facilities. NIH HL062881 (HG) and HL118524 (HG), (H.L.) funded this research.
Publisher Copyright:
© 2017
PY - 2017/7
Y1 - 2017/7
N2 - Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome, characterized by increased diastolic stiffness and a preserved ejection fraction, with no effective treatment options. Here we studied the therapeutic potential of exercise for improving diastolic function in a mouse model with HFpEF-like symptoms, the TtnΔIAjxn mouse model. TtnΔIAjxn mice have increased diastolic stiffness and reduced exercise tolerance, mimicking aspects of HFpEF observed in patients. We investigated the effect of free-wheel running exercise on diastolic function. Mechanical studies on cardiac muscle strips from the LV free wall revealed that both TtnΔIAjxn and wildtype (WT) exercised mice had a reduction in passive stiffness, relative to sedentary controls. In both genotypes, this reduction is due to an increase in the compliance of titin whereas ECM-based stiffness was unaffected. Phosphorylation of titin's PEVK and N2B spring elements were assayed with phospho-site specific antibodies. Exercised mice had decreased PEVK phosphorylation and increased N2B phosphorylation both of which are predicted to contribute to the increased compliance of titin. Since exercise lowers the heart rate we examined whether reduction in heart rate per se can improve passive stiffness by administering the heart-rate-lowering drug ivabradine. Ivabradine lowered heart rate in our study but it did not affect passive tension, in neither WT nor TtnΔIAjxn mice. We conclude that exercise is beneficial for decreasing passive stiffness and that it involves beneficial alterations in titin phosphorylation.
AB - Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome, characterized by increased diastolic stiffness and a preserved ejection fraction, with no effective treatment options. Here we studied the therapeutic potential of exercise for improving diastolic function in a mouse model with HFpEF-like symptoms, the TtnΔIAjxn mouse model. TtnΔIAjxn mice have increased diastolic stiffness and reduced exercise tolerance, mimicking aspects of HFpEF observed in patients. We investigated the effect of free-wheel running exercise on diastolic function. Mechanical studies on cardiac muscle strips from the LV free wall revealed that both TtnΔIAjxn and wildtype (WT) exercised mice had a reduction in passive stiffness, relative to sedentary controls. In both genotypes, this reduction is due to an increase in the compliance of titin whereas ECM-based stiffness was unaffected. Phosphorylation of titin's PEVK and N2B spring elements were assayed with phospho-site specific antibodies. Exercised mice had decreased PEVK phosphorylation and increased N2B phosphorylation both of which are predicted to contribute to the increased compliance of titin. Since exercise lowers the heart rate we examined whether reduction in heart rate per se can improve passive stiffness by administering the heart-rate-lowering drug ivabradine. Ivabradine lowered heart rate in our study but it did not affect passive tension, in neither WT nor TtnΔIAjxn mice. We conclude that exercise is beneficial for decreasing passive stiffness and that it involves beneficial alterations in titin phosphorylation.
UR - http://www.scopus.com/inward/record.url?scp=85019881633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019881633&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2017.04.006
DO - 10.1016/j.yjmcc.2017.04.006
M3 - Article
C2 - 28476659
AN - SCOPUS:85019881633
SN - 0022-2828
VL - 108
SP - 24
EP - 33
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -