Thick Filament Based Regulation and the Determinants of Force Generation

Muscle regulation requires both the newly discovered thick filament as well as classical thin filament regulation mechanisms. Thick filament-based regulation mechanisms are generally conceived as processes modulating the number of myosin heads capable of force generation. It has been generally assumed that the biochemical and structural states of myosin, usually correlated with each other, is the basis of this recruitment, and work jointly to regulate contractile force. This notion has been challenged recently by studies showed that the biochemical and structural states of myosin can be decoupled. Here we studied the steady state and dynamic mechanical changes in skinned porcine myocardium with and without OM or piperine to help decipher the basis of thick filament regulation and how either affects contractile force. Our study supports the notion that thick filament activation is primarily a process of myosin recruitment and that it is not necessarily coupled with chemo-cycling of crossbridges. Perturbations that result in myosin head recruitment from the thick filaments do not necessarily increase contractile force and vice versa. These new insights into thick filament activation mechanisms will be of great relevance to better designing sarcomere therapies aimed at reversing them for treatment of myopathies.