Force-Dependent Recruitment from the Myosin Off State Contributes to Length-Dependent Activation

Abstract

Cardiac muscle develops more force when it is activated at longer lengths. The concentration of Ca 2þ required to develop half-maximal force also decreases. These effects are known as length-dependent activation and are thought to play critical roles in the Frank-Starling relationship and cardiovascular homeostasis. The molecular mechanisms underpinning length-dependent activation remain unclear, but recent experiments suggest that they may include recruitment of myosin heads from the off (sometimes called super-relaxed) state. This manuscript presents a mathematical model of muscle contraction that was developed to investigate this hypothesis. Myosin heads in the model transitioned between an off state (that could not interact with actin), an on state (that could bind to actin), and a single attached state. Simulations were fitted to experimental data using multidimensional parameter optimization. Statistical analysis showed that a model in which the rate of the off-to-on transition increased linearly with force reproduced the length-dependent behavior of chemically permeabilized myocardium better than a model with a constant off-to-on transition rate (F-test, p < 0.001). This result suggests that the thick-filament transitions are modulated by force. Additional calculations showed that the model incorporating a mechanosensitive thick filament could also reproduce twitch responses measured in a trabecula stretched to different lengths. A final set of simulations was then used to test the model. These calculations predicted how reducing passive stiffness would impact the length dependence of the calcium sensitivity of contractile force. The prediction (a 60% reduction in DpCa 50 ) mimicked the 58% reduction in DpCa 50 in myocardium from rats that expressed a giant isoform of titin and had low resting tension. Together, these computational results suggest that force-dependent recruitment of myosin heads from the thick-filament off state contributes to length-dependent activation and the Frank-Starling relationship.

Muscle thixotropy—where are we now?

“…For example, interactions with myosin binding protein-C stabilize the OFF state (61) whereas phosphorylation of regulatory light chain shifts the equilibrium toward the ON state (40). The transition is also sensitive to mechanics (27,55,77) with recent simulations modeling length-dependent activation in myocardium, suggesting that the rate of the OFF to ON transition increases with muscle force (14). A similar mechanism in skeletal muscle would have significant implications for short-range stiffness and thixotropy in skeletal muscle.…”

Length-Dependent Activation of Contractility and Ca-Transient Kinetics in Auxotonically Contracting Isolated Rat Ventricular Cardiomyocytes

“…This might be closely related to the progressively increased amplitude of auxotonic shortening in a stretched cell and the enhanced shorteninginduced attenuation and acceleration of the twitch (Hanft et al, 2008;Iribe et al, 2014). Also, this shortening-induced inactivation of myofilaments may be linked to titin-based modulation of Ca 2+ -troponin interaction (Li et al, 2019) and/ or force-dependent recruitment of strong-bound myosin crossbridges (Campbell et al, 2018). As a result, a positive effect of increased preload and a negative effect of shortening counteract and provide little SL-related variation of timing characteristics in auxotonically beating cells.…”

Biophysically detailed mathematical models of multiscale cardiac active mechanics

“…We notice that both models predict the tension-dependent prolongation of the twitch time [43,86,94], as it can be seen from the normalized traces reported in the bottom lines of PLOS COMPUTATIONAL BIOLOGY the figures. We remark that, despite recent measurements on rabbit cells show that part of the increase of twitch force is linked to a larger calcium release under stretch [59], in this paperdue to the lack of experimental data showing a similar effect in human cells-we employ for simplicity the same calcium transient for all lengths.…”