Omecamtiv mecarbil (OM), a direct myosin motor activator, is currently being tested as a therapeutic replacement for conventional inotropes in heart failure (HF) patients. It is known that HF patients exhibit dysregulated β-adrenergic signaling and decreased cardiac myosin-binding protein C (cMyBPC) phosphorylation, a critical modulator of myocardial force generation. However, the functional effects of OM in conditions of altered cMyBPC phosphorylation have not been established. Here, we tested the effects of OM on force generation and cross-bridge (XB) kinetics using murine myocardial preparations isolated from wild-type (WT) hearts and from hearts expressing S273A, S282A, and S302A substitutions (SA) in the M domain, between the C1 and C2 domains of cMyBPC, which cannot be phosphorylated. At submaximal Ca2+ activations, OM-mediated force enhancements were less pronounced in SA than in WT myocardial preparations. Additionally, SA myocardial preparations lacked the dose-dependent increases in force that were observed in WT myocardial preparations. Following OM incubation, the basal differences in the rate of XB detachment (krel) between WT and SA myocardial preparations were abolished, suggesting that OM differentially affects the XB behavior when cMyBPC phosphorylation is reduced. Similarly, in myocardial preparations pretreated with protein kinase A to phosphorylate cMyBPC, incubation with OM significantly slowed krel in both the WT and SA myocardial preparations. Collectively, our data suggest there is a strong interplay between the effects of OM and XB behavior, such that it effectively uncouples the sarcomere from cMyBPC phosphorylation levels. Our findings imply that OM may significantly alter the in vivo cardiac response to β-adrenergic stimulation.
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March 10 2021
cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation
Ranganath Mamidi
,
Ranganath Mamidi
*
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
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Joshua B. Holmes
,
Joshua B. Holmes
*
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
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Chang Yoon Doh
,
Chang Yoon Doh
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
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Katherine L. Dominic
,
Katherine L. Dominic
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
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Nikhil Madugula
,
Nikhil Madugula
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
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Julian E. Stelzer
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Correspondence to Julian E. Stelzer: julian.stelzer@case.edu
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Ranganath Mamidi
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Joshua B. Holmes
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Chang Yoon Doh
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Katherine L. Dominic
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Nikhil Madugula
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Julian E. Stelzer
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH
Correspondence to Julian E. Stelzer: julian.stelzer@case.edu
*
R. Mamidi and J.B. Holmes contributed equally to this paper.
This work is part of a special collection on myofilament function and disease.
Received:
November 02 2020
Accepted:
January 27 2021
Online Issn: 1540-7748
Print Issn: 0022-1295
© 2021 Mamidi et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2021) 153 (7): e202012816.
Article history
Received:
November 02 2020
Accepted:
January 27 2021
Citation
Ranganath Mamidi, Joshua B. Holmes, Chang Yoon Doh, Katherine L. Dominic, Nikhil Madugula, Julian E. Stelzer; cMyBPC phosphorylation modulates the effect of omecamtiv mecarbil on myocardial force generation. J Gen Physiol 5 July 2021; 153 (7): e202012816. doi: https://doi.org/10.1085/jgp.202012816
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