Abstract for Paper IV

The Frank–Starling Law of the Heart; Cross-bridge recruitment and Ca2+ cooperativity

There are two categories of Ca2+ binding involved in cardiac muscle activation; i) The well recognized and understood cardiac troponin-C (Tn-C) Ca2+ binding that is not inhibited by Mg2+ and is easily measured by 45Ca2+ binding and ii) a transient Ca2+-binding site which is ATP-dependent and competitively inhibited by Mg2+. This second Ca2+ binding is restricted to initiation, i.e. cross-bridge recruitment, and thus is not measurable by 45Ca2+ binding. We propose that the structural changes resulting from muscle stretch, particularly with cardiac muscle, obviate the need for the second Ca2+ binding for cross-bridge recruitment. This results in the manifestation of the Frank–Starling “Law of the Heart”. From this we conclude that the stretch-induced increase in Ca2+ sensitivity is in fact a result of decreased Ca2+ cooperativity, contrary to current belief. Predictions are made regarding the interaction of stretch with the substrates or products of the actomyosin-ATPase reaction on the strength of contraction. These predictions have already been observed, although not previously explained. The cross-bridge recruitment control of muscle contraction implies a processive, or walking, movement of the two-headed myosin II along the thin-filaments. Furthermore, these considerations have major implications in muscle relaxation, cardiac Ca2+-sensitizing drugs and the relationship of these to diastolic heart failure.