Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility

Autor: Richard J. Gilbert, Thomas C. Irving, David M. Warshaw, Sakthivel Sadayappan, Weikang Ma, James W. McNamara, Gina Kuffel, Mayandi Sivaguru, Diederik W. D. Kuster, Paul M.L. Janssen, Burns C. Blaxall, Mohit Kumar, Dana M. Leichter, John N. Lorenz, Kyounghwan Lee, Michael J. Previs, Roger Craig, Michelle L. Nieman, Brian Lin, Thomas L. Lynch, Rohit R. Singh, Pieter P. de Tombe, Aaron M. Gibson, Michael J. Zilliox, Owen P. Leary
Přispěvatelé: Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiology, ACS - Heart failure & arrhythmias
Rok vydání: 2021
Předmět:
Zdroj: Lynch, T L, Kumar, M, McNamara, J W, Kuster, D W D, Sivaguru, M, Singh, R R, Previs, M J, Lee, K H, Kuffel, G, Zilliox, M J, Lin, B L, Ma, W, Gibson, A M, Blaxall, B C, Nieman, M L, Lorenz, J N, Leichter, D M, Leary, O P, Janssen, P M L, de Tombe, P P, Gilbert, R J, Craig, R, Irving, T, Warshaw, D M & Sadayappan, S 2021, ' Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility ', Journal of Molecular and Cellular Cardiology, vol. 156, pp. 33-44 . https://doi.org/10.1016/j.yjmcc.2021.03.009
Journal of Molecular and Cellular Cardiology
Journal of Molecular and Cellular Cardiology, Elsevier, 2021, 156, pp.33-44. ⟨10.1016/j.yjmcc.2021.03.009⟩
J Mol Cell Cardiol
Journal of Molecular and Cellular Cardiology, 156, 33-44. Academic Press Inc.
ISSN: 0022-2828
1095-8584
DOI: 10.1016/j.yjmcc.2021.03.009
Popis: International audience; Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N′)-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N′-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N′-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.
Databáze: OpenAIRE
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