Impact of Hypertrophic Cardiomyopathy Mutations on Myosin Catalytic ATPase Activity

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Impact of Hypertrophic Cardiomyopathy Mutations on Myosin Catalytic ATPase Activity

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2018

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Hypertrophic Cardiomyopathy (HCM) is a cardiac defect causing the thickening of the ventricular walls. Cardiac myosin thick filaments are hypothesized to isomerize in the relaxed state (RX) and interact with actin thin filaments during the force generation cycle. The Super Relaxed state (SRX) is a hypothesized inactive state where myosin heads are structurally occluded from the force generation cycle, contributing to myocyte relaxation. We hypothesize that RLC mutations associated with HCM, specifically E22K and R58Q, disrupt cardiac myocyte relaxation through disruption of the myosin Super Relaxed state (SRX). We aimed to expand on previous studies examining HCM mutations to determine the functional impact of HCM mutations on myosin catalytic activity. We hypothesized that the functional disruption of the SRX by HCM associated mutations can be observed by an increase in ATPase activity. Both basal and actin-activated ATPase assays were conducted to determine the activity of the RLC samples in the presence and absence of actin. HMM myosin with RLC samples (hcRLC, R58Q hcRLC, and E22K hcRLC, showed an increase in basal ATPase activity in HCM mutated hcRLC compared to native hcRLC. The presence of actin was shown to activate myosin activity in both native RLC and HCM mutated RLC. The results support the hypothesis that HCM mutations on myosin RLC disrupt the SRX, however, there are additional variables to consider for the mechanisms of cardiac myocyte hyper-contractility associated with HCM.

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This research was supported by the Undergraduate Research Opportunities Program (UROP).

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Byrapuneni, Sriya. (2018). Impact of Hypertrophic Cardiomyopathy Mutations on Myosin Catalytic ATPase Activity. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/199878.

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