THICK-FILAMENT REGULATORY INTERACTIONS IN THE CARDIAC SARCOMERE

Kyrah Turner

Cardiovascular disease remains the leading cause of mortality in the United States, contributing to 1 in 5 of all deaths. Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease that can lead to decreased cardiac output, arrhythmias, and sudden death. Despite its frequency, patients with HCM have limited therapeutic options. While the causes of cardiovascular disease are multi-factorial, contractile deficits at the molecular level play a major role in cardiac dysfunction and may lead to pathological remodeling of the heart. The heart is comprised of several contractile proteins that work together to facilitate contraction, powering blood flow throughout the body. One of the defining properties of cardiac muscle is the Frank-Starling mechanism, which ensures that the volume of blood ejected from the heart during systole matches the volume that enters during diastole, thereby maintaining contractility on a beat-to-beat basis. At the cellular level, length-dependent activation (LDA) underlies the Frank-Starling mechanism. LDA is described by increased force and Ca2+-sensitivity as sarcomere length increases. While the molecular underpinnings of LDA are not fully understood, LDA and therefore the Frank-Starling mechanism are notably diminished during cardiac disease. Thus, understanding how contractile proteins contribute to LDA, and therefore overall cardiac function, is an essential step in developing effective therapeutics to benefit patient care. Cardiac myosin binding protein-C (cMyBP-C) is a commonly mutated protein in HCM clinical cases. Regulatory light chain (RLC) is a regulatory protein located in the myosin neck region. Both cMyBP-C and RLC undergo post-translational phosphorylation to alter protein function. Thick-filament proteins, such as cMyBP-C and RLC, and their interactions remain understudied and poorly understood. This dissertation assesses both: i) individual contributions from the thick-filament proteins cMyBP-C and RLC, and ii) interactions between the thick-filament proteins cMyBP-C and RLC on cardiac remodeling and cardiac muscle contraction. cMyBP-C knockout mouse models demonstrate that the loss of cMyBP-C promotes cellular signaling which initiates morphological remodeling of the myocardium as disease consistent with HCM progresses. Phosphorylation of RLC alters myosin head conformation and nucleotide handling rates, thereby increasing force and calcium sensitivity in a length-dependent manner. When assessing the combined contributions of the proteins, RLC phosphorylation amplified the effect of Ca2+-sensitivity in the cMyBP-C knockout mouse model. These findings suggest that cMyBP-C and RLC interact in a length- and phosphorylation-dependent manner and that this interaction may be essential for contractility in the healthy heart. Together, these studies provide an innovative look at thick-filament regulatory contributions to the cardiac sarcomere, advancing the knowledge in the field and providing groundwork for future therapeutic development.

THICK-FILAMENT REGULATORY INTERACTIONS IN THE CARDIAC SARCOMERE

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