Biophysical Society Thematic Meeting | Canterbury 2023

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

Poster Abstracts

22-POS Board 22 CONTRIBUTION OF THICK FILAMENT STIFFNESS TO LENGTH DEPENDENT ACTIVATION IN CARDIAC MUSCLE Bradley M Palmer 1 ; Anthony L Hessel 2 ; 1 University of Vermont, Molecular Physiology and Biophysics, Burlington, VT, USA 2 University of Muenster, Institute of Physiology II, Muenster, Germany Striated muscle features the property of length dependent activation (LDA), which is observed as an increase in contractile force and myofilament calcium sensitivity with increasing sarcomere length (SL). Although the molecular mechanism that underlies LDA is not fully understood, it’s well recognized that otherwise unavailable myosin heads are lifted or activated from the thick filament upon its sensing sarcomere stretch via titin. The thick filament also stretches as much as ~1.5% at long SL or with activated force, and thick filament stiffness is concomitantly enhanced 10-100 fold. We asked if this increase in thick filament stiffness due to stretch contributes to LDA by enhancing the transmission efficiency of myosin crossbridge force. To answer this question, we generated a computer model of a half thick filament experiencing forces due to thick filament stretch (F m ), myosin crossbridges (F xb ), and the extensible region of titin (F e ). Using published results, the force-stretch characteristics of rat cardiac muscle thick filaments and of rat cardiac titin were compiled, and thick filament stretch was then calculated to satisfy a force balance F m = F xb + F e over a range of simulated calcium activation. We found that, if the stiffness of the myosin S2 segment is linear, LDA does not emerge within increasing SL. However, if myosin S2 segment demonstrates increased stiffness in proportion to thick filament stretch, key features of LDA appear. Specifically, maximal developed force is enhanced ~12% as SL is increased from 1.8 to 2.2 mm. Furthermore, apparent calcium sensitivity, pCa 50 , is enhanced by ~0.02 units, and the apparent Hill coefficient, n, is reduced by ~0.3, as often reported with LDA. These results suggest that the non-linear stiffness characteristics of the thick filament and myosin S2 segment plausibly contribute to LDA in striated muscle.

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