Modeling thick filament activation suggests a molecular basis for force depression

Area of Science:

• Muscle physiology
• Biophysics
• Computational biology

Background:

• Developing multiscale models for muscle function is challenging due to limited self-consistent data.
• Connecting molecular and cellular muscle mechanics requires integrated experimental and modeling approaches.

Purpose of the Study:

• To create and validate a self-consistent multiscale model of muscle fiber mechanics.
• To link single muscle fiber force responses to myosin-actin molecular interactions.
• To investigate the mechanisms underlying residual force enhancement and force depression.

Main Methods:

• Measured force responses of skinned rabbit psoas muscle fibers to ramp shortenings and step stretches.
• Performed single-molecule and ensemble measurements of myosin-actin interactions using laser trapping and in vitro motility assays.
• Developed a partial differential equation model incorporating thick filament activation, series and parallel elastic elements, and titin-actin interactions.

Main Results:

• Optimized model parameters using a subset of fiber measurements.
• The model accurately predicted remaining fiber measurements and molecular assay data.
• The model captured residual force enhancement and force depression phenomena.

Conclusions:

• The developed multiscale data are self-consistent and suitable for testing other models.
• The model provides a molecular mechanism for force depression involving thick filament activation and a parallel elastic element.
• This work advances the understanding of muscle force regulation across multiple scales.