Key result
Cooperative cardiac thin filament activation involves complex interactions among cMyBP-C, cRLC, and titin.
Why the study?
Detailed knowledge of sarcomere regulatory processes is critical to understanding mechanisms sustaining physiological cardiac function, defining cardiac disorders, and developing sarcomere-directed therapies.
Detailed knowledge of sarcomere control processes is critical for understanding physiological cardiac states, defining cardiac disorders, and developing targeted therapies.
Refines sarcomere regulation models; leaves open targeted therapies for cardiac disorders pending validation.
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.
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Solı́s et al. (2021) conducted a review in Cardiac thin filament activation. This review highlights that cooperative activation of cardiac thin filaments involves complex interactions among sarcomere functional domains, including cMyBP-C, cRLC, and titin.
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