Biophysical Society Thematic Meeting | Canterbury 2023

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

Monday Speaker Abstracts

RAMP-STRETCHES DURING RELAXATION OF TWITCHING INTACT CARDIAC TRABECULA SUGGEST A NEED FOR DYNAMIC MODELS OF MYOFILAMENT FUNCTION Bertrand C Tanner 1 ; Bradley M Palmer 2 ; Charles S Chung 3 ; 1 Washington State University, Integrative Physiology and Neuroscience, Pullman, WA, USA 2 University of Vermont, Molecular Physiology and Biophysics, Burlington, VT, USA 3 Wayne State University, Physiology, Detroit, MI, USA We have previously found that relaxation is dependent on the strain rate of a lengthening stretch just prior to relaxation, also referred to as Mechanical Control of Relaxation. To investigate the mechanisms underlying Mechanical Control of Relaxation, we sought to characterize experimentally induced ramp-stretches using existing models of stress-responses to muscle stretch. Ramp-stretches of varying strain rates (amplitude=1% muscle length) were applied to intact rat cardiac trabeculae following a load-clamp at 50% of the maximal developed twitch force, which provide a first-order estimate of ejection and coupling to an afterload. The resultant stress-response was calculated as the difference between the time-dependent stress profile between load-clamped twitches with and without a ramp-stretch. The stress-response exhibited features of the step-stretch response of activated, permeabilized myocardium, such as distortion dependent peak stress, rapid force decay related to crossbridge detachment, and stress recovery related to crossbridge recruitment. The peak stress was strain rate dependent, but the minimum stress and the time-to-minimum stress values were not. As the stretches occurred later into diastole, a more passive stress-response was observed. Three mathematical models with parameters representing crossbridge attachment and detachment kinetics were fit to the stretch responses to assess whether crossbridge kinetics showed a strain rate-dependence, as predicted by prior studies (Kawai and Brandt 1980, Palmer et al 2007, Palmer et al 2020). An explicit strain-dependence in the kinematic model suggests that crossbridge detachment rates increase as strain rates increase, but all models showed some limitation the fits, especially near the nadir of the stress response. A substantive limitation of these models is likely the assumption of constant calcium and thin filament activation. Additionally, models including more explicit (fewer lumped) parameters and/or time-varying changes (Smith and Geeves 1995, Campbell 2014) may provide improved mechanistic insight into strain-rate dependent changes of myofilaments during relaxation.

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