Activation and Relaxation Kinetics in Skeletal and Cardiac Muscles

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A large amount of data is available on the Ca2+ regulation of the thin filament of skeletal and cardiac muscle, but some general concepts are still under debate. To quantitatively describe muscle contraction and relaxation in the 3D multi-sarcomere geometry we have implemented in computational platform MUSICO: (i) a nine state actomyosin ATPase cycle, (ii) extensibility of thick and thin filaments, (iii) the kinetics of Ca2+ binding to TnC involving two (skeletal) or one (cardiac) calcium binding sites and (iv) the McKillop-Geeves and the continuous-flexible-chain models of thin filament regulation. Simulated force-pCa relations closely follow the observations in skeletal and cardiac muscles. Interestingly, the higher Hill coefficient observed in cardiac muscle requires a longer confined persistence length (stiffer Tm) or a weaker interaction of Tm with actin. Note that confined persistence length increases with increase of Tm stiffness and decreases with strength of interaction of Tm with actin. The simulations also predicted delayed rapid muscle relaxation after a decrease of calcium concentration to pre- contraction level. The relaxation delay time was much shorter in cardiac muscle than in skeletal muscle. This is due to lower level of maximal activation of cardiac muscle compared to skeletal muscle, and therefore fewer TmTn units with more than one myosin bound. But the cardiac muscle takes a longer time to relax completely. These differences can be clearly seen in a comparison of cardiac and skeletal muscle twitch contractions. Using the same parameters, the simulations predicted the rise of force during the twitch but relaxation was slower than predicted by simulations, especially in cardiac muscle. This discrepancy invites further investigation of the interplay between the actomyosin cycle and calcium regulation via TmTn chain interactions with actin.Supported by: NIH R01s AR048776 and DC 011528