Factors Beyond Detachment Kinetics that Influence Unloaded Shortening Velocities of Muscle

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Recent studies demonstrate the influence of actin-myosin attachment kinetics on in vitro actin filament sliding velocities (V), but it is unclear what factors determine whether velocities are detachment (d/τon) or attachment limited (Yengo et al. 2012. J Muscle Res Cell Motil.). We have developed a muscle model with molecular detail that suggests three key mechanisms by which attachment kinetics can influence unloaded shortening velocities. First, the saturation of myosin binding sites on actin by weakly bound myosin heads can result in attachment limited velocities that are slower than the detachment limit. Essentially, at high myosin densities the actin-activated ATPase activity (attachment limited) in the motility assay saturates before mechanical saturation (detachment limited). Second if actin-bound myosin heads that resist actin movement have a relatively low stiffness, unloaded shortening velocities can exceed the detachment limit. The non-linear compliance of positively and negatively strained myosin heads was demonstrated experimentally (Kaya and Higuchi. 2010. Science. 329: 686-9). Finally, our model shows that mechanically accelerated ADP release kinetics can result in velocities that exceed the detachment limit. These simulations accurately describe the observation of hypermotile velocities (Hooft et al. 2007. Biochemistry. 46:3513-20., Jackson and Baker. 2009. PCCP. 11:4808-14.). In summary, unloaded shortening velocities can be influenced by many factors other than detachment kinetics. Thus a mutation or perturbation that results in a change in V need not result from a change in only d or τon.