Novel insights into sarcomere regulatory systems control of cardiac thin filament activation

Abstract

Our review focuses on sarcomere regulatory mechanisms with a discussion of cardiac-specific modifications to the three-state model of thin filament activation from a blocked to closed to open state. We discuss modulation of these thin filament transitions by Ca2+, by crossbridge interactions, and by thick filament–associated proteins, cardiac myosin–binding protein C (cMyBP-C), cardiac regulatory light chain (cRLC), and titin. Emerging evidence supports the idea that the cooperative activation of the thin filaments despite a single Ca2+ triggering regulatory site on troponin C (cTnC) cannot be considered in isolation of other functional domains of the sarcomere. We discuss long- and short-range interactions among these domains with the regulatory units of thin filaments, including proteins at the barbed end at the Z-disc and the pointed end near the M-band. Important to these discussions is the ever-increasing understanding of the role of cMyBP-C, cRLC, and titin filaments. Detailed knowledge of these control processes is critical to the understanding of mechanisms sustaining physiological cardiac state with varying hemodynamic load, to better defining genetic and acquired cardiac disorders, and to developing targets for therapies at the level of the sarcomeres.

Effects of Sarcomere Activators and Inhibitors Targeting Myosin Cross-Bridges on Ca2+-Activation of Mature and Immature Mouse Cardiac Myofilaments

“…3B; Table 1), Ca 2+ -sensitivity as quantified by the pCa 50 (-log of the half-maximally activating molar Ca 2+ concentration) (Fig. 3C; Table 1), and the steepness of the curves, reflecting cooperative activation (Arteaga et al, 2000;Solis and Solaro, 2021) and quantified by nH, the Hill coefficient (Fig. 3D; Table 1).…”

“…Cardiac contraction and relaxation are controlled by sarcomeres expressing different protein isoforms in mature and immature myofilaments. A dominant isoform switch occurs in cardiac troponin (Tn), a thin filament hetero-trimeric complex that together with tropomyosin (Tm) controls the Ca 2+ -dependent reaction of thin filaments with force generating myosin crossbridges (Solaro et al, 2013;Solis and Solaro, 2021). The mechanism of action for OM and Mava has been attributed to their modification of the state of myosin cross-bridges, effectively adding or removing the number of myosin heads that can participate in shortening and force generation (Green et al, 2016;Teerlink et al, 2021).…”

Further progress in understanding of myofibrillar function in health and disease

“…The authors propose that mavacamten may alter the interplay between thick and thin filament regulatory mechanisms of contraction, and that this includes a stabilization of myosin motor heads in autoinhibited states. Solís and Solaro (2021) review the sarcomere regulatory mechanisms and focus on cardiac-specific modifications to the three-state model of thin filament activation. The authors discuss modulation by Ca 2+ , cross-bridges, cMyBP-C, cardiac RLC (cRLC), and titin.…”

“… Solís and Solaro (2021) review the sarcomere regulatory mechanisms and focus on cardiac-specific modifications to the three-state model of thin filament activation. The authors discuss modulation by Ca 2+ , cross-bridges, cMyBP-C, cardiac RLC (cRLC), and titin.…”

NH2-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors

“…for its action as the inhibitory unit of the heterotrimeric Tn complex, which together with cardiac troponin T (cTnT), the tropomyosin (Tm) binding unit, and cardiac troponin C (cTnC), the Ca 2+ -binding unit, act to modify the of Tm-actin interaction in regulating the on-off state of thin filaments in sarcomere activation and relaxation [6,7]. In diastole, cTnI structures located in an inhibitory peptide (Ip) and at the mobile COOH-domain interact strongly with actin and Tm and promote protein-protein interactions with cTnT-Tm to establish an inhibited state with Tm blocking the reaction of cross-bridges with actins (Figure 1).…”