The long-range goal of this proposal is to define the mechanisms by which mutations in cardiac myosin binding protein C (MyBPC) cause hypertrophic (HCM) and dilated cardiomyopathy (DCM), a disease that affects 0.2% of the population worldwide, and is the leading cause of sudden death in young adults. Mutations in MyBPC are among the most common causes of inherited cardiomyopathy accounting for more than 40% of all known cases, and are associated with heart failure and sudden cardiac arrest. Because MyBPC is a critical modulator of actomyosin interactions, the initial functional deficit caused by mutations in MyBPC is expected to manifest as a defect in the regulation of cardiac muscle contraction at the myofilament level. However, the precise molecular mechanisms by which mutations in MyBPC alter contractile function and cause disease are not understood, and it has yet to be established if MyBPC expressing mutations can incorporate into the sarcomere to directly alter contractile function. A lack of fundamental insights into how MyBPC mutations cause HCM and DCM severely limits our ability to devise effective therapies to overcome the disease and its functional consequences. The proposed experiments will elucidate the functional effects of mutations in MyBPC known to cause a range of disease severity in children and adults, and will test the hypothesis that missense mutations in MyBPC incorporate into the sarcomere to directly alter contractile function in three principal aims designed to: 1) Establish the functional effects of MyBPC mutations on the Ca2+-dependencies of steady-state force and dynamic cross-bridge function in cardiac fibers reconstituted with MyBPC expressing HCM and DCM causing mutations, 2) Define the effects of MyBPC mutations on ATPase activity, thin filament regulation of force generation, and cross-bridge kinetics, using steady-state and transient kinetic analysis of fluorescently labeled proteins, and 3) Determine the in vivo functional consequences of missense mutations in MyBPC by assessing ventricular structure and function using pressure-volume catheterization and high resolution cardiac magnetic resonance imaging in animals subjected to acute gene transfer of mutant MyBPC. It is expected that results from these integrative studies will provide novel insights of the underlying mechanisms by which mutations in MyBPC cause cardiac dysfunction and will aid in the development of novel therapeutic strategies for treatment MyBPC related HCM and DCM.

Public Health Relevance

Familial hypertrophic cardiomyopathy (FHC) is highly prevalent inherited cardiac disease and is the most common cause of sudden death in adolescents and young adults. Mutations in cardiac myosin binding protein C (MyBPC) are a leading cause of H+FHC in humans, however the mechanisms by which these mutations cause disease are not understood. This proposal will address this important deficiency in our understanding of the mechanisms of MyBPC related FHC, specifically, how they affect cardiac muscle function. Results from these studies will contribute to the development of novel therapies to improve cardiac function in MyBPC related FHC.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Case Western Reserve University
Schools of Medicine
United States
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Li, Jiayang; Gresham, Kenneth S; Mamidi, Ranganath et al. (2018) Sarcomere-based genetic enhancement of systolic cardiac function in a murine model of dilated cardiomyopathy. Int J Cardiol 273:168-176
Mamidi, Ranganath; Li, Jiayang; Doh, Chang Yoon et al. (2018) Impact of the Myosin Modulator Mavacamten on Force Generation and Cross-Bridge Behavior in a Murine Model of Hypercontractility. J Am Heart Assoc 7:e009627
Mamidi, Ranganath; Gresham, Kenneth S; Li, Jiayang et al. (2017) Cardiac myosin binding protein-C Ser302 phosphorylation regulates cardiac ?-adrenergic reserve. Sci Adv 3:e1602445
Mamidi, Ranganath; Li, Jiayang; Gresham, Kenneth S et al. (2017) Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium. Circ Heart Fail 10:
Mamidi, Ranganath; Gresham, Kenneth S; Verma, Sujeet et al. (2016) Cardiac Myosin Binding Protein-C Phosphorylation Modulates Myofilament Length-Dependent Activation. Front Physiol 7:38
Gresham, Kenneth S; Stelzer, Julian E (2016) The contributions of cardiac myosin binding protein C and troponin I phosphorylation to ?-adrenergic enhancement of in vivo cardiac function. J Physiol 594:669-86
Mamidi, Ranganath; Gresham, Kenneth S; Li, Amy et al. (2015) Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C. J Mol Cell Cardiol 85:262-72
Mamidi, Ranganath; Li, Jiayang; Gresham, Kenneth S et al. (2014) Cardiac myosin binding protein-C: a novel sarcomeric target for gene therapy. Pflugers Arch 466:225-30
Mamidi, Ranganath; Gresham, Kenneth S; Stelzer, Julian E (2014) Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation. Front Physiol 5:461
Gresham, Kenneth S; Mamidi, Ranganath; Stelzer, Julian E (2014) The contribution of cardiac myosin binding protein-c Ser282 phosphorylation to the rate of force generation and in vivo cardiac contractility. J Physiol 592:3747-65

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