The role of contractile unit reorganization in force generation in airway smooth muscle.

Airway smooth muscle (ASM) cells undergo remodelling and reside in a tissue structure that is subject to heterogenous stress distributions that change dynamically during the breathing cycle. In this paper, we develop a structural model of an ASM cell that consists of contractile units (actin and myosin filaments) in series and parallel, anchored to a nonlinearly elastic cytoskeleton. We mimic a typical experimental protocol that involves isometric force generation through triggering of the contractile machinery, followed by oscillatory length fluctuation of the cell. We use the model to predict the effect of a single instance of rearrangement of the contractile machinery, combined with strain-stiffening of the cytoskeleton, on the force generated by the sarcomeres, and the total force generated by the cell. By linking intra-cellular events to whole-cell behaviour, the model reveals mechanistic relationships between structural properties and cell-level force-length loops. We show how contractile force, shortening velocity and sarcomere operating lengths vary as the internal cell architecture is altered. Additionally, we show how interactions between the internal contractile machinery and cytoskeletal structure play a role in the regulation of force generation and hysteresis of the cell.