Fitting a model to multiscale data suggests thick filament activation can produce force depression in muscle fibers.

Abstract

Multiscale muscle models aim to connect muscle's molecular and organ-scale function to, e.g., inform the treatment of muscle diseases. Current muscle models have not quantitatively fit data spanning the molecular to cellular scales due, in part, to a lack of self-consistent multiscale data. To address this gap, we measured the force response from single skinned rabbit psoas muscle fibers to ramp shortenings (5% amplitude) and step stretches (0.25%, 0.5%, 0.75% amplitude), performed on the plateau region of the force-length relationship. We isolated myosin from the same muscle source and, under similar conditions, performed single molecule and mini ensemble measurements of event duration and displacement using optical trapping and in vitro motility assays. We fit the fiber data by developing a partial differential equation model that includes thick filament activation, whereby an increase in force on the thick filament pulls myosin out of the superrelaxed state, a series elastic element and a parallel elastic element. This parallel elastic element models a titin-actin interaction proposed to account for the increase in isometric force following stretch (residual force enhancement). By optimizing the model fit to fiber measurements, we specified seven unknown parameters. The model then successfully predicted our molecular measurements from the optical trap and in vitro motility at different ATP concentrations. The success of the model suggests that our multiscale data are self-consistent and can serve as a testbed for other multiscale modeling efforts. Moreover, the model captures the decrease in isometric force observed in our muscle fibers after active shortening (force depression), suggesting a molecular mechanism for force depression, whereby a parallel elastic element combined with thick filament activation serve to decrease the number of cycling cross-bridges.