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

AbstractWe examined the influence of cross-bridge cycling kinetics on the length dependence of steady-state force and the rate of force redevelopment (ktr) during Ca2+-activation at sarcomere lengths (SL) of 2.0 and 2.3μm 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 (Fmax) and Ca2+-sensitivity of force (pCa50) and reduced the cooperativity (nH) of force-pCa relations, whereas reducing [ATP] to 0.5mM (low ATP) increased pCa50 and nH without changing Fmax. The difference in pCa50 between SL 2.0 and 2.3μm (ΔpCa50) was comparable between ATP and dATP, but reduced with low ATP. Maximal ktr was elevated by dATP and reduced by low ATP. Ca2+-sensivity of ktr increased with both dATP and low ATP and was unaffected by altered SL under all conditions. Significantly, at equivalent levels of submaximal force ktr 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