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Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature.
Biophys J 2019; 116(11):2149-2160BJ

Abstract

Heart failure is a life-threatening condition that occurs when the heart muscle becomes weakened and cannot adequately circulate blood and nutrients around the body. Omecamtiv mecarbil (OM) is a compound that has been developed to treat systolic heart failure via targeting the cardiac myosin heavy chain to increase myocardial contractility. Biophysical and biochemical studies have found that OM increases calcium (Ca2+) sensitivity of contraction by prolonging the myosin working stroke and increasing the actin-myosin cross-bridge duty ratio. Most in vitro studies probing the effects of OM on cross-bridge kinetics and muscle force production have been conducted at subphysiological temperature, even though temperature plays a critical role in enzyme activity and cross-bridge function. Herein, we used skinned, ventricular papillary muscle strips from rats to investigate the effects of [OM] on Ca2+-activated force production, cross-bridge kinetics, and myocardial viscoelasticity at physiological temperature (37°C). We find that OM only increases myocardial contractility at submaximal Ca2+ activation levels and not maximal Ca2+ activation levels. As [OM] increased, the kinetic rate constants for cross-bridge recruitment and detachment slowed for both submaximal and maximal Ca2+-activated conditions. These findings support a mechanism by which OM increases cardiac contractility at physiological temperature via increasing cross-bridge contributions to thin-filament activation as cross-bridge kinetics slow and the duration of cross-bridge attachment increases. Thus, force only increases at submaximal Ca2+ activation due to cooperative recruitment of neighboring cross-bridges, because thin-filament activation is not already saturated. In contrast, OM does not increase myocardial force production for maximal Ca2+-activated conditions at physiological temperature because cooperative activation of thin filaments may already be saturated.

Authors+Show Affiliations

Department of Integrative Physiology and Neuroscience.Department of Integrative Physiology and Neuroscience.Department of Integrative Physiology and Neuroscience; Washington Center for Muscle Biology, Washington State University, Pullman, Washington. Electronic address: bertrand.tanner@wsu.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31103235

Citation

Kieu, Thinh T., et al. "Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature." Biophysical Journal, vol. 116, no. 11, 2019, pp. 2149-2160.
Kieu TT, Awinda PO, Tanner BCW. Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature. Biophys J. 2019;116(11):2149-2160.
Kieu, T. T., Awinda, P. O., & Tanner, B. C. W. (2019). Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature. Biophysical Journal, 116(11), pp. 2149-2160. doi:10.1016/j.bpj.2019.04.020.
Kieu TT, Awinda PO, Tanner BCW. Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature. Biophys J. 2019 Jun 4;116(11):2149-2160. PubMed PMID: 31103235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Omecamtiv Mecarbil Slows Myosin Kinetics in Skinned Rat Myocardium at Physiological Temperature. AU - Kieu,Thinh T, AU - Awinda,Peter O, AU - Tanner,Bertrand C W, Y1 - 2019/04/25/ PY - 2018/07/16/received PY - 2019/04/10/revised PY - 2019/04/15/accepted PY - 2020/06/04/pmc-release PY - 2019/5/20/pubmed PY - 2019/5/20/medline PY - 2019/5/20/entrez SP - 2149 EP - 2160 JF - Biophysical journal JO - Biophys. J. VL - 116 IS - 11 N2 - Heart failure is a life-threatening condition that occurs when the heart muscle becomes weakened and cannot adequately circulate blood and nutrients around the body. Omecamtiv mecarbil (OM) is a compound that has been developed to treat systolic heart failure via targeting the cardiac myosin heavy chain to increase myocardial contractility. Biophysical and biochemical studies have found that OM increases calcium (Ca2+) sensitivity of contraction by prolonging the myosin working stroke and increasing the actin-myosin cross-bridge duty ratio. Most in vitro studies probing the effects of OM on cross-bridge kinetics and muscle force production have been conducted at subphysiological temperature, even though temperature plays a critical role in enzyme activity and cross-bridge function. Herein, we used skinned, ventricular papillary muscle strips from rats to investigate the effects of [OM] on Ca2+-activated force production, cross-bridge kinetics, and myocardial viscoelasticity at physiological temperature (37°C). We find that OM only increases myocardial contractility at submaximal Ca2+ activation levels and not maximal Ca2+ activation levels. As [OM] increased, the kinetic rate constants for cross-bridge recruitment and detachment slowed for both submaximal and maximal Ca2+-activated conditions. These findings support a mechanism by which OM increases cardiac contractility at physiological temperature via increasing cross-bridge contributions to thin-filament activation as cross-bridge kinetics slow and the duration of cross-bridge attachment increases. Thus, force only increases at submaximal Ca2+ activation due to cooperative recruitment of neighboring cross-bridges, because thin-filament activation is not already saturated. In contrast, OM does not increase myocardial force production for maximal Ca2+-activated conditions at physiological temperature because cooperative activation of thin filaments may already be saturated. SN - 1542-0086 UR - https://www.unboundmedicine.com/medline/citation/31103235/Omecamtiv_Mecarbil_Slows_Myosin_Kinetics_in_Skinned_Rat_Myocardium_at_Physiological_Temperature L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3495(19)30338-8 DB - PRIME DP - Unbound Medicine ER -