Half-Sarcomeres with Heterogeneous Crossbridge Populations can be Stabilized by Accompanying Variations in Titin Filaments

Abstract

Residual force enhancement occurs when the steady-state force produced by a contracting muscle is increased following stretch even though the average actin-myosin overlap within sarcomeres is reduced. We recently used a computational model to examine the mechanical properties of a system of serially-connected half-sarcomeres. The simulations demonstrated that such a model exhibits force enhancement when the active force generating capacity of the individual half-sarcomeres (the number of functioning myosin heads) varies by as little as 2% (Campbell et al., PLoS Comput Biol 2011). Variability at this level would be hard to detect in real experiments but is difficult to discount in biological systems. We have now performed additional simulations in which we vary the passive mechanical properties of the individual half-sarcomeres (the non-linear stiffness of their titin filaments) as well as their active mechanics. The results show that when both active and passive properties are varied, lengths of half-sarcomeres prior to stretch do not always correlate with post-stretch values. This finding may explain experimental observations of ‘stronger’ (shorter) half-sarcomeres prior to stretch that yield to a greater degree than ‘weaker’ (longer) half-sarcomeres. Data published by other groups (Labeit et al., PNAS 2003; Bagni et al., Biophys J 2002) suggest that the stiffness of titin molecules increases with the intracellular Ca2+ concentration. We predict that when we add Ca2+-dependent titin stiffness to our model it will further stabilize half sarcomeres after stretch (reduce half-sarcomere length variability). This might help to prevent stretch-induced damage, thus increasing the resiliency of the contractile system. A computational model that combines active and passive half-sarcomere variability with a Ca2+-activated stiffness may therefore offer a more complete explanation of residual force enhancement and related phenomena.