The Role Of Titin In Cardiac Function: Studies With The Mouse Model Deficient In The Splicing Factor RBM20
AuthorMethawasin, Mei Methajit
AdvisorGranzier, Hendrikus L.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © 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.
AbstractIn the first half of this work, titin's role in cardiac function was studied using intact cardiac myocytes. The development of a carbon fiber based cell-attachment system allowed diastolic and systolic function of the isolated intact myocyte to be investigated. Addition of actomyosin inhibitor to the intact myocyte revealed that the majority of the cell's diastolic stiffness is due to titin but that actomyosin interaction exists as well and contributes ~ 30% of total diastolic stiffness. The details of this study are provided in chapter 1. Heart failure with preserved ejection fraction (HFpEF) accounts for up to 50% of total heart failure cases and is characterized by increased diastolic stiffness. An effective treatment for HFpEF does not exist. Reducing titin stiffness as a therapeutic strategy for lowering left ventricular (LV) chamber stiffness in HFpEF is currently under consideration. To understand the functional consequence of reduced titin stiffness on global cardiac function a Rbm20 Δᴿᴿᴹ mouse model was created. The Rbm20 Δᴿᴿᴹ model has deficiency in titin splicing that results in expression of very large and compliant titin isoforms in the sarcomeres. Study of Rbm20 Δᴿᴿᴹ cells revealed that cellular diastolic stiffness was inversely related to the size of titin and was reduced in a graded manner in Rbm20 Δᴿᴿᴹ heterozygous (+/-) and homozygous (-/-) cells. Importantly, reduced titin-based stiffness manifested in vivo as reduced LV chamber stiffness, which could be observed by echocardiography and pressure volume (PV) analysis. The systolic function of Rbm20 Δᴿᴿᴹ was studied by measuring the Frank-Starling mechanism (FSM), first at the intact myocyte level. The FSM was reduced in Rbm20 Δᴿᴿᴹ +/- and -/- with the largest reduction in -/- cells. PV analysis demonstrated a reduced FSM at the LV chamber level, consistent with the result at the cellular level. Surprisingly, exercise testing showed an enhanced exercise performance in cardiac specific Rbm20 Δᴿᴿᴹ +/- mice (relative to wild-type mice). Thus, this work indicates that increasing titin compliance improves diastolic function but negatively impacts systolic function. Importantly, findings suggest that the beneficial effect of improving diastolic function is a dominant effect. This work is described in Chapter 2.
Degree ProgramGraduate College