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Title: Structural and functional impact of troponin C-mediated Ca 2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle

Abstract

Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca 2+ sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca 2+-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca 2+ sensitizer. Our findings suggest that both methods of increasing myofilament Ca 2+ sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (k TR); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I 1,1-1/I 1,0 ratio from X-ray diffraction. Computational modeling suggests that Ca 2+ sensitization through this cTnC mutation or bepridil accelerates k TR primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in k(TR), we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca 2+ activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controlsmore » force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca 2+ sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca 2+ activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [1];  [2]; ORCiD logo [4]; ORCiD logo [1]
  1. Florida State Univ., Tallahassee, FL (United States). Dept. of Biomedical Sciences
  2. Illinois Inst. of Technology, Chicago, IL (United States). Dept. of Biological Sciences
  3. Illinois Inst. of Technology, Chicago, IL (United States). Dept. of Biological Sciences; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS), X-Ray Science Division
  4. Florida State Univ., Tallahassee, FL (United States). Dept. of Biological Science
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
OSTI Identifier:
1505173
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Molecular and Cellular Cardiology
Additional Journal Information:
Journal Volume: 123; Journal Issue: C; Journal ID: ISSN 0022-2828
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Ca2+ sensitivity; bepridil; cardiac thin filament; hypertrophic cardiomyopathy; kinetics of tension redevelopment; myofilament lattice spacing; sinusoidal stiffness; small-angle x-ray diffraction; thin filament; troponin C

Citation Formats

Gonzalez-Martinez, David, Johnston, Jamie R., Landim-Vieira, Maicon, Ma, Weikang, Antipova, Olga, Awan, Omar, Irving, Thomas C., Bryant Chase, P., and Pinto, J. Renato. Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle. United States: N. p., 2018. Web. doi:10.1016/j.yjmcc.2018.08.015.
Gonzalez-Martinez, David, Johnston, Jamie R., Landim-Vieira, Maicon, Ma, Weikang, Antipova, Olga, Awan, Omar, Irving, Thomas C., Bryant Chase, P., & Pinto, J. Renato. Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle. United States. doi:10.1016/j.yjmcc.2018.08.015.
Gonzalez-Martinez, David, Johnston, Jamie R., Landim-Vieira, Maicon, Ma, Weikang, Antipova, Olga, Awan, Omar, Irving, Thomas C., Bryant Chase, P., and Pinto, J. Renato. Mon . "Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle". United States. doi:10.1016/j.yjmcc.2018.08.015. https://www.osti.gov/servlets/purl/1505173.
@article{osti_1505173,
title = {Structural and functional impact of troponin C-mediated Ca2+ sensitization on myofilament lattice spacing and cross-bridge mechanics in mouse cardiac muscle},
author = {Gonzalez-Martinez, David and Johnston, Jamie R. and Landim-Vieira, Maicon and Ma, Weikang and Antipova, Olga and Awan, Omar and Irving, Thomas C. and Bryant Chase, P. and Pinto, J. Renato},
abstractNote = {Acto-myosin cross-bridge kinetics are important for beat-to-beat regulation of cardiac contractility; however, physiological and pathophysiological mechanisms for regulation of contractile kinetics are incompletely understood. Here we explored whether thin filament-mediated Ca2+ sensitization influences cross-bridge kinetics in permeabilized, osmotically compressed cardiac muscle preparations. We used a murine model of hypertrophic cardiomyopathy (HCM) harboring a cardiac troponin C (cTnC) Ca2+-sensitizing mutation, Ala8Val in the regulatory N-domain. We also treated wild-type murine muscle with bepridil, a cTnC-targeting Ca2+ sensitizer. Our findings suggest that both methods of increasing myofilament Ca2+ sensitivity increase cross-bridge cycling rate measured by the rate of tension redevelopment (kTR); force per cross-bridge was also enhanced as measured by sinusoidal stiffness and I1,1-1/I1,0 ratio from X-ray diffraction. Computational modeling suggests that Ca2+ sensitization through this cTnC mutation or bepridil accelerates kTR primarily by promoting faster cross-bridge detachment. To elucidate if myofilament structural rearrangements are associated with changes in k(TR), we used small angle X-ray diffraction to simultaneously measure myofilament lattice spacing and isometric force during steady-state Ca2+ activations. Within in vivo lattice dimensions, lattice spacing and steady-state isometric force increased significantly at submaximal activation. We conclude that the cTnC N-domain controls force by modulating both the number and rate of cycling cross-bridges, and that the both methods of Ca2+ sensitization may act through stabilization of cTnC's D-helix. Furthermore, we propose that the transient expansion of the myofilament lattice during Ca2+ activation may be an additional factor that could increase the rate of cross-bridge cycling in cardiac muscle. These findings may have implications for the pathophysiology of HCM.},
doi = {10.1016/j.yjmcc.2018.08.015},
journal = {Journal of Molecular and Cellular Cardiology},
number = C,
volume = 123,
place = {United States},
year = {2018},
month = {10}
}

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