Cardiac Length Dependence of Force and Force Redevelopment Kinetics with Altered Cross-Bridge Cycling

Abstract

We examined the influence of cross-bridge cycling kinetics on the length dependence of steady-state force and the rate of force redevelopment ( k tr) during Ca 2+-activation at sarcomere lengths (SL) of 2.0 and 2.3 μm in skinned rat cardiac trabeculae. Cross-bridge kinetics were altered by either replacing ATP with 2-deoxy-ATP (dATP) or by reducing [ATP]. At each SL dATP increased maximal force ( F max) and Ca 2+-sensitivity of force (pCa 50) and reduced the cooperativity ( n H) of force-pCa relations, whereas reducing [ATP] to 0.5 mM (low ATP) increased pCa 50 and n H without changing F max. The difference in pCa 50 between SL 2.0 and 2.3 μm (ΔpCa 50) was comparable between ATP and dATP, but reduced with low ATP. Maximal k tr was elevated by dATP and reduced by low ATP. Ca 2+-sensivity of k tr increased with both dATP and low ATP and was unaffected by altered SL under all conditions. Significantly, at equivalent levels of submaximal force k tr was faster at short SL or increased lattice spacing. These data demonstrate that the SL dependence of force depends on cross-bridge kinetics and that the increase of force upon SL extension occurs without increasing the rate of transitions between nonforce and force-generating cross-bridge states, suggesting SL or lattice spacing may modulate preforce cross-bridge transitions.