| Summary: | Airway smooth muscle (ASM) regulates flow resistance in the airways of the lung. Dysfunction of the smooth muscle is implicated in the exaggerated airway narrowing seen in asthma, possibly due to adaptation of ASM to excessively short lengths. In this study, we examined the behaviour of ASM in its adaptation to large changes in cell length and the underlying mechanisms for its ability to adapt and regain optimal contractility. Isometric force measured immediately after a length change revealed that the amount of decrease in force after the length change was very sensitive to the direction of the length change (more sensitive in release than in stretch), and relatively insensitive to the absolute lengths from/to which the muscle was stretched or released. Force decreased by 20.4±0.9 (%) when muscle length was doubled from an arbitrarily chosen reference length (Lref, at which the muscle had been adapted); in the reversed direction with a halving of 2xLref, the decrease in force was 48.0±2.3 (%). Quantification of myosin filament density by electron microscopy revealed a similar asymmetry; a length increase from Lref to 1.6xLref resulted in no significant decrease in filament density, but a length decrease from 1.6xLref to Lref left only 81.0± 3.3 (%) of the filaments intact (P<0.05). Velocity measurements after step changes in length revealed that velocity was proportional to muscle length, and the change in velocity was almost instantaneous after the length change (without full adaptation). We have developed a model to explain all the above results. It appears that length change leads to an immediate reconfiguration of the actin filament lattice so that the number of contractile units (appropriate to length) can be formed. Formation of myosin filaments within the actin filament lattice appears to be a separate process, which requires a longer time and tends to influence force and not velocity. === Medicine, Faculty of === Medicine, Department of === Experimental Medicine, Division of === Graduate
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