Modulation of Cardiac Titin Stiffness in Physiological and Pathophysiological States

The giant sarcomeric protein titin spans the length of the half sarcomere and contains an I-band spanning region that functions as a molecular spring that develops passive force during diastole. Titin stiffness is modulated both by isoform switching and post-translational modifications including phosphorylation. Modulation of titin stiffness occurs in physiological and pathophysiological states including Heart Failure with Preserved Ejection Fraction (HFpEF) which is marked by increased diastolic stiffness. Here, I investigated the effects of titin phosphorylation by two kinases, ERK2 and CaMKIIδ, at the level of the protein and the myocardium. Additionally, I used mouse models of HFpEF to test if modulating titin stiffness could ameliorate increased diastolic stiffness. Specifically, I used the TAC/DOCA model (surgical) and the N2B KO model (genetic) of HFpEF to test the effects of metformin on titin stiffness and diastolic function. HFpEF mice treated with metformin had improved diastolic function, reduced passive stiffness, and increased PKA phosphorylation compared to non-treated HFpEF animals. Interestingly, these results were only found in animals with an intact N2B-element indicating an underlying mechanism that arises from the N2B element and that includes an increase in PKA-phosphorylation. Additionally, I used the TtnΔIAjxn mouse model, as a mechanical analog of the increased diastolic stiffness in HFpEF, to test the therapeutic effects of exercise and heart rate reduction. Exercise induced hypo-phosphorylation of the PEVK element of titin consistent with reduced passive tension while heart-rate reduction had no effect on passive stiffness. These studies build on the increasing understanding of how titin's stiffness can be modulated and the ways to take advantage of titin in a beneficial manner for diastolic function.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Graduate College

Grantor dc:publisher

The University of Arizona.

Year dc:date.issued

2016

Author dc:creator

• Slater, Rebecca E.

Advisor dc:contributor.advisor

• Granzier, Henk

Committee members dc:contributor.committeemember

• Granzier, Henk
• Harris, Samantha
• Tardiff, Jill
• Yoon, Jeong-Yeol

Statement dc:rights

• Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10150/623160

OAI identifier oai:identifier

oai:repository.arizona.edu:10150/623160