Regulated Model of Steady-State Cardiac Length-Dependent Activation

Abstract

Recent data suggests length-dependent activation derives from titin interacting with super-relaxed myosin crossbridges on the thick filament. This feature was incorporated into an existing model of crossbridge dynamics (Caremani et al, 2015) by replacing the detached post-ATP-hydrolysis state with an equilibrium mixture of rapidly interacting super-relaxed, detached, and weakly bound crossbridges. The model also included: (1) cooperative activation of the thin filament by both Ca++ and strongly bound crossbridges, (2) loosely coupled interaction that allows Ca++ to dissociate from troponin C (TnC) before strong crossbridges detach, (3) Ca++ bound more strongly to TnC when a strong crossbridge is also bound nearby. As suggested by data (Sun & Irving, 2015), the equilibrium between super-relaxed and detached crossbridges equaled 3:1 for a long sarcomere length. We supposed that the reduced forces exerted by titin on the thick filament at low sarcomere length made it more likely to form a super-relaxed crossbridge. As the force exerted by titin increases, the super-relaxed myosin transitions to an unfettered detached state and becomes available to form weak crossbridges. We altered the Gibbs free energy to form a super-relaxed crossbridge by less than 1 kT as titin's force decreased over sarcomere lengths from 2.25 to 1.9 µm. This caused the maximal steady-state force for isometric contraction at saturating Ca++ to reduce by ∼ 25%, as data suggests (Dobesh et al, 2002). The model thus unites existing data and provides a more quantitative understanding of how titin interacts with the thick filament at different sarcomere lengths. We anticipate that this model insight and more extensive data will lead to deeper understanding of cardiac length-dependent activation. (Supported by the Center for Engineering MechanoBiology through a grant from NSF's STC program (CMMI):15-48571).