Multiscale Studies Of Skeletal Muscle Contraction

Sarcomeres,which are the basic contractile units of skeletal muscles,are made of two distinct types of filaments,thick filaments and thin filaments.During muscle shortening,myosins protruding from the thick filament interact cyclically with the thin filament,driving the relative sliding of two filaments.Unveiling the behaviors of skeletal muscle contraction can help to reveal the working mechanism of myosin motors,to understand the mechanism of motor's collective function and to investigate various cellular activities,such as cell division,ciliary and flagellar beating,cellular mechanosensing,and intracellular transport.In this dissertation,by adopting a multiple scale method,we investigate the mechanism of muscle contraction.The results may be used to design synthetic motors with high energy efficiency.The main contents are listed below:(1)We investigate the respective contribution of ATP hydrolysis cycle and bond breaking to motor force regulation by simulations.Four different cases of sarcomere contraction are studied with the steady-state mechanical model.The results indicate that as long as attached motors can detach from the actin filament through the ATP hydrolysis cycle,the number of working motors will be proportional to the filament load and the motor force is well regulated.In contrast,when attached motors can only detach from actin filaments as catch-slip bonds,the motor force persistently increases with the filament load.(2)Based on the structural analysis,we develop the transitional state model of myosin motor to investigate the effect of temperature on the power stroke of a single myosin.The results suggest that the motor force varies little before the completion of the working stroke,while it decreases linearly with the relative sliding distance between thin and thick filaments when the power stroke is exhausted.We also find that,though the isometric force and the maximal stroke size depend heavily on the temperature,the effect of temperature on the releasable elastic energy can be dispensable.(3)Based on a kinetic model for the chemomechanical cycle of single myosin,the cumulative distribution of the durations of bound events is calculated.These quantitative results indicate that there exists an inherent coupling between bond breaking and state transition.As myosins may adopt much higher transition rates than bond breaking rates at different nucleotide states,the coupling leads to high apparent detachment rates of a single motor.(4)By integrating the transitional state model of a single myosin motor,we propose a transient state model for sarcomere contraction.The model can help to link the behaviors of sarcomere contraction to those of a single myosin motor.We then simulate the sarcomere contraction with the model.The results show that,with the increase of the applied load,the shortening velocity decreases,while the number of working motors increases.In the high-load region the force per attached motor remains almost constant.The tendencies agree well with experimental observations.The transient state model can be employed to study the force transient or velocity transient process of muscle contraction,and also be adapted for the study of the kinetics during cellular rigidity sensing of a substrate.