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    Sarcomere length-dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin

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    Author
    Li, King-Lun
    Methawasin, Mei
    Tanner, Bertrand C W
    Granzier, Henk L
    Solaro, R John
    Dong, Wen-Ji
    Affiliation
    Univ Arizona, Dept Cellular & Mol Med
    Issue Date
    2019-01-07
    
    Metadata
    Show full item record
    Publisher
    ROCKEFELLER UNIV PRESS
    Citation
    Li, K. L., Methawasin, M., Tanner, B. C., Granzier, H. L., Solaro, R. J., & Dong, W. J. (2019). Sarcomere length–dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin. The Journal of general physiology, 151(1), 30-41.
    Journal
    JOURNAL OF GENERAL PHYSIOLOGY
    Rights
    © 2018 Li et al.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Cardiac performance is tightly regulated at the cardiomyocyte level by sarcomere length, such that increases in sarcomere length lead to sharply enhanced force generation at the same Ca2+ concentration. Length-dependent activation of myofilaments involves dynamic and complex interactions between a multitude of thick- and thin-filament components. Among these components, troponin, myosin, and the giant protein titin are likely to be key players, but the mechanism by which these proteins are functionally linked has been elusive. Here, we investigate this link in the mouse myocardium using in situ FRET techniques. Our objective was to monitor how length-dependent Ca2+-induced conformational changes in the N domain of cardiac troponin C (cTnC) are modulated by myosin-actin cross-bridge (XB) interactions and increased titin compliance. We reconstitute FRET donor- and acceptor-modified cTnC(13C/51C)AEDANS-DDPM into chemically skinned myocardial fibers from wild-type and RBM20-deletion mice. The Ca2+-induced conformational changes in cTnC are quantified and characterized using time-resolved FRET measurements as XB state and sarcomere length are varied. The RBM20-deficient mouse expresses a more compliant N2BA titin isoform, leading to reduced passive tension in the myocardium. This provides a molecular tool to investigate how altered titin-based passive tension affects Ca2+-troponin regulation in response to mechanical stretch. In wild-type myocardium, we observe a direct association of sarcomere length-dependent enhancement of troponin regulation with both Ca2+ activation and strongly bound XB states. In comparison, measurements from titin RBM20-deficient animals show blunted sarcomere length-dependent effects. These results suggest that titin-based passive tension contributes to sarcomere length-dependent Ca2+-troponin regulation. We also conclude that strong XB binding plays an important role in linking the modulatory effect of titin compliance to Ca2+-troponin regulation of the myocardium.
    ISSN
    1540-7748
    PubMed ID
    30523116
    DOI
    10.1085/jgp.201812218
    Version
    Final published version
    Sponsors
    American Heart Association [17GRNT33460153, 17SDG33370153]; National Institutes of Health [R01HL80186, R01HL118524, HL115988, PO1HL624026]; National Science Foundation [1656450]
    Additional Links
    http://jgp.rupress.org/content/early/2018/12/05/jgp.201812218?versioned=true
    ae974a485f413a2113503eed53cd6c53
    10.1085/jgp.201812218
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