# Nanometer scale difference in myofilament lattice structure of muscle alters muscle function in a spatially explicit model

## TL;DR

This study shows that small changes in the structure of muscle filaments can significantly affect muscle function during dynamic movements.

## Contribution

The first spatially explicit model that includes radial crossbridge dependence to produce realistic muscle mechanical function during dynamic oscillations.

## Key findings

- Mechanical function (net work) in muscle depends on the lattice spacing during dynamic oscillations.
- A 1 nm change in lattice spacing can switch muscle function from motor-like to brake-like.
- The model can simulate work loops similar to those observed in the hawkmoth Manduca sexta.

## Abstract

Crossbridge binding, state transitions, and force in active muscle is dependent on the radial spacing between the myosin-containing thick filament and the actin-containing thin filament in the filament lattice. This radial spacing has been previously shown through spatially explicit modeling and experimental efforts to greatly affect quasi-static, isometric, force production in muscle. It has recently been suggested that this radial spacing might also be able to drive differences in mechanical function, or net work, under dynamic oscillations like those which occur in muscles in vivo. However, previous spatially explicit models either had no radial spacing dependence, meaning the radial spacing could not be investigated, or did include radial spacing dependence but could not reproduce in vivo net work during dynamic oscillations and only investigated isometric contractions. Here we show the first spatially explicit model to include radial crossbridge dependence which can produce mechanical function similar to real muscle. Using this spatially explicit model of a half sarcomere, we show that when oscillated at strain amplitudes and frequencies like those in the main flight muscles of the hawkmoth Manduca sexta, mechanical function (net work) does depend on the lattice spacing. In addition, since the trajectory of lattice spacing changes during dynamic oscillation can vary from organism to organism, we can prescribe a trajectory of lattice spacing changes in the spatially explicit half sarcomere model and investigate the extent to which the time course of lattice spacing changes can affect mechanical function. We simulated a half sarcomere undergoing dynamic oscillations and prescribed the Poisson’s ratio of the lattice to be either 0 (constant lattice spacing) or 0.5 (isovolumetric lattice spacing changes). We also simulated net work using lattice spacing data taken from M. sexta which has a variable Poisson’s ratio. Our simulation results indicate that the lattice spacing can change the mechanical function of muscle, and that in some cases a 1 nm difference can switch the net work of the half sarcomere model from positive (motor-like) to negative (brake-like).

The myosin motors which are responsible for force generation in muscle not only produce axial force, but also produce radial force which can deform the myofilament lattice. Previous spatially explicit models investigated how this radial force and lattice spacing might influence isometric force, but were not able to generate net work under dynamic, phasically activated oscillations like those in in vivo muscle, known as work loops. Here we revise a previous spatially explicit model and use it to investigate how the structure of the lattice spacing can affect whole muscle mechanical function during simulated work loops.