Cardiac Length-Dependent Activation: Weak Binding Hypothesis Tested by a Computational Sarcomere Model

Abstract

Experiments suggest that length changes alter activation in cardiac sarcomeres within a few milliseconds (Mateja & deTombe, 2012). Thus, the mechanism producing length-dependent activation must occur early in the contractile cycle, such as during the formation of weakly bound crossbridges. We hypothesized that a decrease in the energy required to form weak crossbridges would lead to greater probability of their formation. Such decrease in energy at longer sarcomere lengths could occur via reduction in both: (1) radial distance a crossbridge stretches to attach to actin, due to lattice spacing; (2) radial elastic crossbridge stiffness, due to influence of sarcomere length on modulators such as titin, myosin light chains, or myosin binding protein-C. We have previously developed a compact kinetic model of cardiac sarcomere dynamics (Hunter, BPS Meeting 2015). Parameters in this model were adjusted to produce the best fit with five experimental measures at constant sarcomere length (from others’ published data): (1) F-pCa relation, (2) alteration in F-pCa with addition of NEM-S1 strong crossbridges, (3) relation between kinetics of tension recovery and calcium concentration [k(TR)-pCa relation], (4) alteration in k(TR)-pCa with addition of NEM-S1, (5) shape of F-Ca loops during twitches. All five of these sets of experimental data were reasonably matched by the model using the best-fit set of parameters. Holding all other best-fit parameters constant, we then modified just the binding constant for weak crossbridges. An increased binding constant (due to lower energy to form a weak crossbridge) reproduced both of the following effects of increased sarcomere length: (1) shifted mid-point of F-pCa relation to lower [Ca++], (2) increased maximum force at saturating [Ca++]. Both of these experimental effects of increased sarcomere length are well known from published data (Dobesh, Konhilas, deTombe, 2002).