Abstract

Familial cardiomyopathies, including hypertrophic (HCM), restrictive (RCM) and dilated cardiomyopathy (DCM), are the leading cause of sudden cardiac death in young people. These diseases, which are characterized by altered cardiac contractility and remodeling of the heart, can lead to heart failure. These diseases are primarily caused by point mutations in sarcomeric proteins that generate or regulate heart contraction, such as troponin T. In the heart, the troponin complex together with tropomyosin lie along the actin filament and regulate myosin’s ability to bind actin and produce force. Here I show how mutations in troponin T affect contractility at the molecular level leading to differing phenotypes at the cellular level and in patients. At the molecular level, I show that a model troponin-T HCM mutation and RCM mutation result in an increased population of force generating states while a troponin-T DCM mutation causes a decreased population of force generating states. Second, on a more basic science level, I show that the presence of troponin and tropomyosin on actin do not significantly affect the kinetics and mechanics of the cardiac myosin working stroke, which will serve as crucial parameters for accurate modeling of the heart’s force velocity relationship. In total, this work has important implications for our understanding of the molecular mechanism of cardiac muscle contraction and for interpreting the effects of disease-causing mutations in sarcomeric proteins.

Committee Chair

Michael J. Greenberg

Committee Members

Eric Galburt

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Winter 12-15-2021

Language

English (en)

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