Sarcomere length-dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin
AffiliationUniv Arizona, Dept Cellular & Mol Med
MetadataShow full item record
PublisherROCKEFELLER UNIV PRESS
CitationLi, 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.
JournalJOURNAL OF GENERAL PHYSIOLOGY
Rights© 2018 Li et al.
Collection InformationThis 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 firstname.lastname@example.org.
AbstractCardiac 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.
VersionFinal published version
SponsorsAmerican Heart Association [17GRNT33460153, 17SDG33370153]; National Institutes of Health [R01HL80186, R01HL118524, HL115988, PO1HL624026]; National Science Foundation 
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