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 information concerning SL is transduced by the contractile apparatus of muscle is hot known. The overall goal of our research is to elucidate the molecular mechanisms that underlie LDA. The proposed research project is focused around two specific aims. Since we have recently found that inter-filament spacing in a relaxed muscle does not underlie LDA, our first aim is to test the hypothesis that it is inter-filament spacing attained in an active muscle that underlies LDA. Second, we have recently found that troponin, and particularly cardiac troponin-l, plays a pivotal role in LDA. Therefore, in our second aim will determine the role of troponin and cooperative activation in myofilament length dependent activation. We will test the hypothesis that cardiac troponin is sufficient and/or required to impart LDA upon a striated muscle; experiments will be performed using recombinant protein extraction-reconstitution experiments in skinned muscle. 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075494-04
Application #
7452409
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2005-07-01
Project End
2008-10-31
Budget Start
2008-07-01
Budget End
2008-10-31
Support Year
4
Fiscal Year
2008
Total Cost
$4,883
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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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