The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. At the cellular level, sarcomere length (SL) dependent myofilament Ca2+ sensitivity underlies this phenomenon (length dependent activation-LDA). How the contractile apparatus transduces the information concerning SL is not known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. During the previous funding cycle we have found that changes in inter-filament spacing is not the mechanism that underlies LDA. Furthermore, we discovered that cardiac troponin-I is essential for LDA. Preliminary studies now show that interruption of cooperative activation along the thin filament markedly enhances LDA, while a reduction in active cycling cross-bridges does not affect LDA. Together, our findings suggest that the molecular mechanisms that underlie length dependency in muscle are the result of a direct sarcomere length mediated modulation of the structure/function of the thin filament system, myosin and/or thick filament system, or the kinetics/structure of the interaction between actin and myosin. The proposed research project is focused around three specific aims to test whether LDA is the result of modulation at the level of the thin filament, the thick filament or the kinetics of actin-myosin interaction. Overall, we have obtained preliminary data that demonstrate the feasibility of our hypotheses as well as our technical expertise to conduct the proposed experiments. Although the Frank- Starling Law of the Heart constitutes a fundamental property of the heart that has been appreciated for well over a century, the molecular mechanisms that underlie this phenomenon are still incompletely understood. Our research proposal is aimed to enhance our understanding of this important physiological process that controls cardiac performance on a beat-to-beat basis.
The Frank-Starling Law describes the fundamental property of the heart to increase cardiac strength in response to increased filling volume. The cellular mechanism for this phenomenon is an increase in myofilament Ca2+ responsiveness in response to sarcomere stretch via mechanisms that are incompletely understood. We will employ isolated myocardium for biophysical measurements probing at thin and thick filament structure using contractile protein exchange, transgenic murine models, fluorescent probes, as well as x-ray diffraction. The overall aim is to unravel the molecular mechanisms that underlie this important physiological regulatory system operating in the heart on a beat-to- beat basis.
|Dvornikov, Alexey V; de Tombe, Pieter P; Xu, Xiaolei (2018) Phenotyping cardiomyopathy in adult zebrafish. Prog Biophys Mol Biol 138:116-125|
|Ait-Mou, Younss; Zhang, Mengjie; Martin, Jody L et al. (2017) Impact of titin strain on the cardiac slow force response. Prog Biophys Mol Biol 130:281-287|
|de Tombe, Pieter P; ter Keurs, Henk E D J (2016) Cardiac muscle mechanics: Sarcomere length matters. J Mol Cell Cardiol 91:148-50|
|Dvornikov, Alexey V; Smolin, Nikolai; Zhang, Mengjie et al. (2016) Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres. J Biol Chem 291:21817-21828|
|Ait-Mou, Younss; Hsu, Karen; Farman, Gerrie P et al. (2016) Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins. Proc Natl Acad Sci U S A 113:2306-11|
|Kumar, Mohit; Govindan, Suresh; Zhang, Mengjie et al. (2015) Cardiac Myosin-binding Protein C and Troponin-I Phosphorylation Independently Modulate Myofilament Length-dependent Activation. J Biol Chem 290:29241-9|
|Bovo, Elisa; Mazurek, Stefan R; de Tombe, Pieter P et al. (2015) Increased Energy Demand during Adrenergic Receptor Stimulation Contributes to Ca(2+) Wave Generation. Biophys J 109:1583-91|
|Barefield, David; Kumar, Mohit; Gorham, Joshua et al. (2015) Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol 79:234-43|
|Zhang, Mengjie; Martin, Jody L; Kumar, Mohit et al. (2015) Rapid large-scale purification of myofilament proteins using a cleavable His6-tag. Am J Physiol Heart Circ Physiol 309:H1509-15|
|Abrol, Neha; de Tombe, Pieter P; Robia, Seth L (2015) Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban. J Biol Chem 290:7130-40|
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