Coupling of Adjacent Tropomyosins Enhances Cross-Bridge-Mediated Cooperative Activation in a Markov Model of the Cardiac Thin Filament

Abstract

We developed a Markov model of cardiac thin filament activation that accounts for interactions among nearest-neighbor regulatory units (RUs) in a spatially explicit manner. Interactions were assumed to arise from structural coupling of adjacent tropomyosins (Tms), such that Tm shifting within each RU was influenced by the Tm status of its neighbors. Simulations using the model demonstrate that this coupling is sufficient to produce observed cooperativity in both steady-state and dynamic force-Ca(2+) relationships. The model was further validated by comparison with reported responses under various conditions including inhibition of myosin binding and the addition of strong-binding, non-force-producing myosin fragments. The model also reproduced the effects of 2.5 mM added P(i) on Ca(2+)-activated force and the rate of force redevelopment measured in skinned rat myocardial preparations. Model analysis suggests that Tm-Tm coupling potentiates the activating effects of strongly-bound cross-bridges and contributes to force-Ca(2+) dynamics of intact cardiac muscle. The model further predicts that activation at low Ca(2+) concentrations is cooperatively inhibited by nearest neighbors, requiring Ca(2+) binding to >25% of RUs to produce appreciable levels of force. Without excluding other putative cooperative mechanisms, these findings suggest that structural coupling of adjacent Tm molecules contributes to several properties of cardiac myofilament activation.

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Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease

“…To define the precise molecular mechanisms underlying the effects of Mlc2v phosphorylation on muscle contraction, we created a multiscale computational model based on our recent computational model of cooperative myofilament activation (21). This approach allows testing of 2 hypothesized molecular mechanisms for a direct effect of Mlc2v phosphorylation on the kinetics of actin-myosin regulation of striated muscle (Figure 3, A-C).…”

“…We and others have previously reported that positive cooperative mechanisms contribute to several properties of activation of cardiac muscle contraction primarily involving Ca 2+ -mediated activation via actin-bound regulatory proteins involving the cardiac thin filament (9,(21)(22)(23). The question of whether and how myosin regulatory proteins, such as MLC2, influence these cooperative mechanisms and effects in contracting living cardiac muscles remains to be directly addressed.…”

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