Titin-mediated thick filament activation stabilizes myofibrils on the descending limb of their force–length relationship

PURPOSE: The aim of this study was to extend current half-sarcomere models by involving a recently found force-mediated activation of the thick filament and analyze the effect of this mechanosensing regulation on the length stability of half-sarcomeres arranged in series. METHODS: We included a super-relaxed state of myosin motors and its force-dependent activation in a conventional cross-bridge model. We simulated active stretches of a sarcomere consisting of 2 non-uniform half-sarcomeres on the descending limb of the force–length relationship. RESULTS: The mechanosensing model predicts that, in a passive sarcomere on the descending limb of the force–length relationship, the longer half-sarcomere has a higher fraction of myosin motors in the on-state than the shorter half-sarcomere. The difference in the number of myosin motors in the on-state ensures that upon calcium-mediated thin filament activation, the force-dependent thick filament activation keeps differences in active force within 20% during an active stretch. In the classical cross-bridge model, the corresponding difference exceeds 80%, leading to great length instabilities. CONCLUSION: Our simulations suggest that, in contrast to the classical cross-bridge model, the mechanosensing regulation is able to stabilize a system of non-uniform half-sarcomeres arranged in series on the descending limb of the force–length relationship.