Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

13-POS Board 13 MODELLING THE FUNCTIONAL IMPLICATIONS OF THICK-FILAMENT OFF STATE DYNAMICS IN CARDIAC MUSCLE Alexandre Lewalle 1 ; Gregory N Milburn 2 ; Kenneth S Campbell 2 ; Steven A Niederer 1 ; 1 King's College London, Biomedical Engineering, London, United Kingdom 2 University of Kentucky, Department of Physiology, Lexington, KY, USA The regulation of cardiac sarcomere contraction is essential for ensuring physiological function. Conventional descriptions of tension regulation have focused predominantly on thin-filament properties, but growing experimental evidence indicates a complementary thick-filament-based activation. This process involves a structural transformation from a super-relaxed "off" state where myosin heads cannot interact with the actin thin filaments. This transition is itself tension dependent, implying a positive feedback mechanism. The extent to which this mechanism accounts for length-dependent activation (LDA) and the Frank-Starling effect, alongside other sarcomere-level mechanisms, remains to be fully established. This challenge stems, in part, from the non-trivial coupling between strain and stress within the sarcomere, making the distinction between explicit and implicit length dependence ambiguous. Long before the discovery of the off state, some mathematical models of myocyte contraction were implementing length dependence by manually inserting phenomenological strain-dependent terms in, e.g., tension magnitude, calcium sensitivities, or rate constants. Whilst enabling adequate empirical fits to measurements, this ad hoc approach does not necessarily embody specific biophysical mechanisms systematically. The aim of this study was therefore to test whether, in principle, off state dynamics could plausibly account, either fully or partially, for LDA without resorting to ad hoc phenomenological formulations. We amended the Land 2017 ODE contraction model of the human left ventricle to include force-dependent off-state dynamics, and tested its ability to reproduce effective length-dependent steady-state (F-pCa) and dynamic (ktr) behaviour. Our results qualitatively reproduced essential observable features of length-dependent calcium sensitivity, force magnitude, and ktr. We tested and discarded alternative hypothetical feedback scenarios based explicitly on strain. We modelled the off-state-stabilising drug mavacamten, reproducing observed length-dependent steady-state and ktr behaviours. In conclusion, our results support the plausibility of myosin off-state dynamics as a potentially dominant contributor to sarcomere tension regulation and LDA.

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