Increased Titin Compliance Reduced Length-Dependent Contraction and Slowed Cross-Bridge Kinetics in Skinned Myocardial Strips from Rbm20ΔRRM Mice
Author
Pulcastro, Hannah C.Awinda, Peter O.
Methawasin, Mei
Granzier, Henk
Dong, Wenji
Tanner, Bertrand C. W.
Affiliation
Univ Arizona, Dept Cellular & Mol MedIssue Date
2016-07-29Keywords
cross-bridge kineticstitin compliance
length-dependent activation
Frank-Starling relationship
cardiac muscle contraction
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FRONTIERS MEDIA SACitation
Increased Titin Compliance Reduced Length-Dependent Contraction and Slowed Cross-Bridge Kinetics in Skinned Myocardial Strips from Rbm20ΔRRM Mice 2016, 7 Frontiers in PhysiologyJournal
Frontiers in PhysiologyRights
© 2016 Pulcastro, Awinda, Methawasin, Granzier, Dong and Tanner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).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
Titin is a giant protein spanning from the Z-disk to the M-band of the cardiac sarcomere. In the I-band titin acts as a molecular spring, contributing to passive mechanical characteristics of the myocardium throughout a heartbeat. RNA Binding Motif Protein 20 (RBM20) is required for normal titin splicing, and its absence or altered function leads to greater expression of a very large, more compliant N2BA titin isoform in Rbm20 homozygous mice (Rbm20(Delta RRm)) compared to wild-type mice (WT) that almost exclusively express the stiffer N2B titin isoform. Prior studies using Rbm20(Delta RRm) animals have shown that increased titin compliance compromises muscle ultrastructure and attenuates the Frank-Starling relationship. Although previous computational simulations of muscle contraction suggested that increasing compliance of the sarcomere slows the rate of tension development and prolongs cross-bridge attachment, none of the reported effects of Rbm20(Delta RRm) on myocardial function have been attributed to changes in cross-bridge cycling kinetics. To test the relationship between increased sarcomere compliance and cross-bridge kinetics, we used stochastic length-perturbation analysis in Ca2+-activated, skinned papillary muscle strips from Rbrn20<^>R'Rm and WT mice. We found increasing titin compliance depressed maximal tension, decreased Ca2+-sensitivity of the tension-pCa relationship, and slowed myosin detachment rate in myocardium from Rbm20(Delta RRm) vs. WT mice. As sarcomere length increased from 1.9 to 2.2 mu m, length-dependent activation of contraction was eliminated in the Rbrn20<^>R'Rm myocardium, even though myosin MgADP release rate decreased similar to 20% to prolong strong cross-bridge binding at longer sarcomere length. These data suggest that increasing N2BA expression may alter cardiac performance in a length-dependent manner, showing greater deficits in tension production and slower cross-bridge kinetics at longer sarcomere length. This study also supports the idea that passive mechanical characteristics of the myocardium influence ensemble cross-bridge behavior and maintenance of tension generation throughout the sarcomere.ISSN
1664-042XVersion
Final published versionae974a485f413a2113503eed53cd6c53
10.3389/fphys.2016.00322
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Except where otherwise noted, this item's license is described as © 2016 Pulcastro, Awinda, Methawasin, Granzier, Dong and Tanner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).