Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity

Rohit R Singh; Rebecca E Slater; Jinghong Wang; Chen Wang; Qi Guo; Alykhan S Motani; James J Hartman; Sakthivel Sadayappan; Brandon L Ason

doi:10.1016/j.jacbts.2022.04.013

Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity

JACC Basic Transl Sci. 2022 Sep 7;7(10):1021-1037. doi: 10.1016/j.jacbts.2022.04.013. eCollection 2022 Oct.

Authors

Rohit R Singh^{1

2}, Rebecca E Slater¹, Jinghong Wang¹, Chen Wang¹, Qi Guo¹, Alykhan S Motani¹, James J Hartman³, Sakthivel Sadayappan², Brandon L Ason¹

Affiliations

¹ Amgen Research, Department of Cardiometabolic Disorders, Amgen, South San Francisco, California, USA.
² Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio, USA.
³ Discovery Biology, Cytokinetics, South San Francisco, California, USA.

Abstract

Modulation of sarcomere contractility represents a new therapeutic opportunity for the treatment of heart failure by directly targeting the thick and thin filament proteins of the sarcomere to increase cardiac muscle contraction. This study compared the effect of 2 small molecules (M and T) that selectively alter myosin thick filament (M) or troponin thin filament (T) activity on overall cardiac muscle mechanics. This study revealed key differences related to the mechanism utilized by M and T to increase contractile force generation and suggests that targeting different proteins within the sarcomere may result in differentiating therapeutic profiles.

Keywords: AAA, transgenic mice expressing alanine at Serine 273, 282, and 302; DDD, transgenic mice expressing aspartate at Serine 273, 282, and 302; Fmax, maximal force per cross-sectional area; HF, heart failure; KO, knock-out; LV, left ventricle; M, myosin-selective small molecule; MYBPC3; OM, omecamtiv mecarbil; SRX, super relaxed state; T, troponin-selective small molecule; cMyBP-C phosphorylation; cMyBP-C, cardiac myosin binding protein-C; heart failure; ktr, rate of force redevelopment; myosin; pCa50, half maximal effective calcium concentration; tWt, transgenic wild type; troponin.