Length-dependence of Cross-bridge Mediated Activation of the Cardiac Thin Filament

Length-dependent Ca2+activation of the thin filament plays a critical role in the steep force–length relationship of cardiac muscle (Frank-Starling relation). Recent evidence indicates that the increase in myofilament Ca2+sensitivity and Ca2+-troponin C affinity that occurs with increase in sarcomere length results from a cooperative activation of the thin filament by attached cross-bridges. At short sarcomere length the Ca2+sensitivity is lower because the access of cross-bridges for actin is reduced. The aim of this study was to determine the length-dependence of myosin-mediated thin filament activation in skinned bovine ventricular muscle, as assayed by the generation of force with progressive reduction of MgATP concentration in the absence of Ca2+. If the interaction between myosin and actin is weaker at short sarcomere length there should be a lower MgATP concentration needed to maintain the relaxed state. Contrary to expectation, the force–pMgATP relationship was not significantly influenced by change in sarcomere length. However this relationship became length-sensitive in the presence of phosphate analogs which stabilize weak-binding cross-bridges. We suggest that sarcomere length modulates Ca2+sensitivity by controlling the size of the population of thin filament regulatory units in the weakly-bound state.