APPS November 2002 Meeting Abstract 1359

Calcium regulates the development of force in skeletal muscle via processes that include the kinetics of troponin, tropomyosin, and those of cross-bridges. Under steady levels of calcium activation, the relationship between force and calcium is characterised by Hill plots, while a transient level of calcium results in a transient development of isometric force characterised by peak force and the parameters time-to-peak (TTP) and time-to-half-relax (TT1/2R). The model used to simulate this development of muscle force includes kinetics between calcium and regulatory proteins, cooperativity whereby further cross-bridge attachment is potentiated by strongly attached cross-bridges¹, and a three-state mechanism for cycling cross-bridges². Simulations were performed to investigate how the Hill plot and twitch force varied with (i) the calcium sensitivity of TnC, (ii) a uniform change in cross-bridge kinetics, (iii) the level of cooperativity, (iv) the amplitude and speed of the calcium transient. The calcium sensitivity of TnC gave an upper limit for the ca50 of the Hill plot. An increase in the level of cooperativity reduced this ca50 (i.e increased sensitivity), increased the slope (nH) of the Hill plot but did not alter maximum force (Fmax). For a specified calcium transient, an increase in the calcium sensitivity of TnC resulted in a large and slower twitch. An increase in cooperativity, on the other hand, elevated twitch height and left speed unchanged. This was consistent with the potentiating effect of cooperativity on sub-maximal, but not maximal steady state force. A uniform increase in the cross-bridge rate constants resulted in a higher and faster isometric twitch but did not alter the Hill plot. An increase in the amplitude of the calcium transient resulted in a higher and slower twitch force, whereas an increase in the speed of the calcium transient resulted in a faster and smaller twitch force. This investigation gives insight into possible mechanisms through which agents can alter steady-state and transient muscle force.