EFFECTS OF MYOSIN HEAVY CHAIN ISOFORMS AND CARDIOMYOPATHY MUTATIONS ON SARCOMERE LENGTH-DEPENDENT ACTIVATION

Sherif Reda

Heritable mutations in cardiac muscle proteins lead to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. There is a lack of knowledge on how HCM/DCM-related mutations alter the molecular mechanisms governing cardiac muscle function to induce diverse pathological phenotypes and dysfunction. A central mechanism to cardiac muscle function is myofilament length-dependent activation (LDA), whereby an increase in muscle length potentiates myocardial force production. Proper manifestation of LDA is critical for healthy heart function because it underlies the molecular basis by which the heart is able to increase cardiac output in response to increased venous return. Among the important regulatory contractile proteins, myosin heavy chain (MHC) in the thick filament and troponin T (TnT) in the thin filament may confer functional effects to LDA due to their roles in regulating crossbridge (XB) recruitment dynamics. One major limitation to our understanding of LDA in health and disease is that most studies utilize rodent models that predominantly express fast-cycling α-MHC, whereas humans express slow-cycling β-MHC. Kinetic features of MHC isoforms impart unique effects on contractile dynamics, and may therefore modulate LDA. Such observations highlight the need to investigate mechanisms of LDA against a β-MHC background. Therefore, the overall objective of this dissertation is to assess the role of MHC and cardiomyopathy mutations on LDA in adult guinea pig hearts, which naturally express β-MHC. The central hypothesis is that changes in MHC isoform and cardiomyopathy mutations in TnT impact mechanisms governing LDA. We tested our hypothesis by measuring steady-state and dynamic contractile function in detergent-skinned guinea pig cardiac muscle fibers. Specific Aim 1 assessed the effect of altered MHC isoform expression on LDA. Specific Aim 2 investigated the effect of HCM-linked TnT mutation (F88L) on contractile dynamics and LDA. Specific Aim 3 investigated the effect of DCM-linked TnT mutation (R174W) on contractile dynamics and LDA. Regarding MHC, we found that a shift from α- to β-MHC enhanced LDA. Furthermore, HCM and DCM mutations impaired cardiac LDA through distinct mechanisms. This work provides mechanistic insights into the mechanisms governing cardiac muscle LDA, and how such mechanisms manifest in health and disease states.

EFFECTS OF MYOSIN HEAVY CHAIN ISOFORMS AND CARDIOMYOPATHY MUTATIONS ON SARCOMERE LENGTH-DEPENDENT ACTIVATION

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