Calcium sensitivity and myofilament lattice structure in titin N2B KO mice

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Item Type:	Article
Title:	Calcium sensitivity and myofilament lattice structure in titin N2B KO mice
Creators Name:	Lee, E.J., Nedrud, J., Schemmel, P., Gotthardt, M., Irving, T.C. and Granzier, H.L.
Abstract:	The cellular basis of the Frank-Starling "Law of the Heart" is the length-dependence of activation, but the mechanisms by which the sarcomere detects length changes and converts this information to altered calcium sensitivity has remained elusive. Here the effect of titin-based passive tension on the length-dependence of activation (LDA) was studied by measuring the tension-pCa relation in skinned mouse LV muscle at two sarcomere lengths (SLs). N2B KO myocardium, where the N2B spring element in titin is deleted and passive tension is elevated, was compared to WT myocardium. Myofilament lattice structure was studied with low-angle X-ray diffraction; the myofilament lattice spacing (d(10)) was measured as well as the ratio of the intensities of the 1,1 and 1,0 diffraction peaks (I(11)/I(10)) as an estimate of the degree of association of myosin heads with the thin filaments. Experiments were carried out in skinned muscle in which the lattice spacing was reduced with Dextran-T500. Experiments with and without lattice compression were also carried out following PKA phosphorylation of the skinned muscle. Under all conditions that were tested, LDA was significantly larger in N2B KO myocardium compared to WT myocardium, with the largest differences following PKA phosphorylation. A positive correlation between passive tension and LDA was found that persisted when the myofilament lattice was compressed with Dextran and that was enhanced following PKA phosphorylation. Low-angle X-ray diffraction revealed a shift in mass from thin filaments to thick filaments as sarcomere length was increased. Furthermore, a positive correlation was obtained between myofilament lattice spacing and passive tension and the change in I(11)/I(10) and passive tension and these provide possible explanations for how titin-based passive tension might regulate calcium sensitivity.
Keywords:	Cardiac Contraction, Calcium Sensitivity, Titin, Passive Tension, Lattice Structure, Animals, Mice
Source:	Archives of Biochemistry and Biophysics
ISSN:	0003-9861
Publisher:	Academic Press
Volume:	535
Number:	1
Page Range:	76-83
Date:	1 July 2013
Official Publication:	https://doi.org/10.1016/j.abb.2012.12.004
PubMed:	View item in PubMed

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