Contraction of cardiac and skeletal muscle depends in large part on the amount of calcium released from the intracellular calcium store called the sarcoplasmic reticulum (SR).The regulation of this SR calcium is therefore fundamental to heart and muscle performance, and disturbances in the release of this calcium lead to muscle weakness and heart failure. In addition, calcium signaling is involved in the regulation of gene expression that allows striated muscle to adapt to changes in demand or contractile stress. While a detailed understanding of how calcium is released from the SR exists, little is understood about how the stores are replenished. Reports from several groups, including our own, have demonstrated that both cardiac and skeletal muscles are able to sense store depletion and activate calcium entry from the extracellular space in order to replenish the SR (Store operated calcium entry, SOCE). Our preliminary data demonstrate that the recently identified calcium sensor stromal interaction molecule 1 (STIM1) is expressed and functional in striated muscle. Mice lacking a functional STIM1 molecule in the heart demonstrate impaired cardiac function. We hypothesize that STIM1 is critical regulator of the SOC current necessary for repletion of the intracellular stores and required for contractility and calcium dependent gene expression in striated muscle. We therefore propose the following specific aims:
Specific Aim1 : To determine in vitro the role of STIM1 in mediating store operated calcium entry in striated muscle cells;
Specific Aim 2 : To determine in vitro the role of STIM1 in calcium dependent gene expression;
Specific Aim 3 : To determine in vivo the role of STIM1 in regulating store operated calcium entry in cardiac muscle.

Public Health Relevance

The regulation of intracellular calcium is fundamental to the performance of cardiac and skeletal muscle and disturbances in calcium release lead to skeletal muscle and heart failure. Our preliminary data indicates that the calcium sensor stromal interaction molecule 1 (STIM1) is expressed and functional in cardiac and skeletal myocytes and is a critical regulator of calcium within the myocytes. This proposal seeks to further define the function of STIM1 in cardiac and skeletal muscle cells, and to understand its role in cardiac failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL093470-01A1
Application #
7654176
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2009-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$390,000
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Zhang, Hengtao; Sun, Albert Y; Kim, Jong J et al. (2015) STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node. Proc Natl Acad Sci U S A 112:E5618-27
Jayawardena, Tilanthi M; Finch, Elizabeth A; Zhang, Lunan et al. (2015) MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res 116:418-24
Zhao, Guiling; Li, Tianyu; Brochet, Didier X P et al. (2015) STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes. Proc Natl Acad Sci U S A 112:E4792-801
Seeley, Eric J; Rosenberg, Paul; Matthay, Michael A (2013) Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy. J Clin Invest 123:1015-8
Seth, Malini; Li, Tianyu; Graham, Victoria et al. (2012) Dynamic regulation of sarcoplasmic reticulum Ca(2+) stores by stromal interaction molecule 1 and sarcolipin during muscle differentiation. Dev Dyn 241:639-47
Li, Tianyu; Finch, Elizabeth A; Graham, Victoria et al. (2012) STIM1-Ca(2+) signaling is required for the hypertrophic growth of skeletal muscle in mice. Mol Cell Biol 32:3009-17
Stiber, Jonathan A; Tang, Youlan; Li, TianYu et al. (2012) Cytoskeletal regulation of TRPC channels in the cardiorenal system. Curr Hypertens Rep 14:492-7
Jayawardena, Tilanthi M; Egemnazarov, Bakytbek; Finch, Elizabeth A et al. (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 110:1465-73
Eckel, Jason; Lavin, Peter J; Finch, Elizabeth A et al. (2011) TRPC6 enhances angiotensin II-induced albuminuria. J Am Soc Nephrol 22:526-35
Rosenberg, Paul (2011) Socking It to cardiac hypertrophy: STIM1-mediated Ca2+ entry in the cardiomyocyte. Circulation 124:766-8

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