Myosin thick filament lability induced by mechanical strain in airway smooth muscle

Abstract

Airway smooth muscle adapts to different lengths with functional changes that suggest plastic alterations in the filament lattice. To look for structural changes that might be associated with this plasticity, we studied the relationship between isometric force generation and myosin thick filament density in cell cross sections, measured by electron microscope, after length oscillations applied to the relaxed porcine trachealis muscle. Muscles were stimulated regularly for 12 s every 5 min. Between two stimulations, the muscles were submitted to repeated passive +/- 30% length changes. This caused tetanic force and thick-filament density to fall by 21 and 27%, respectively. However, in subsequent tetani, both force and filament density recovered to preoscillation levels. These findings indicate that thick filaments in airway smooth muscle are labile, depolymerization of the myosin filaments can be induced by mechanical strain, and repolymerization of the thick filaments underlies force recovery after the oscillation. This thick-filament lability would greatly facilitate plastic changes of lattice length and explain why airway smooth muscle is able to function over a large length range.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…This interesting response of resting muscle to mechanical strain is transient and appears to be part of the process of the muscle's adaptation to length change. KUO et al [168] have shown that the length-oscillation-induced decrease in force is accompanied by a similar amount of reduction in myosin filament density in the muscle. Transmission of force, therefore, can occur throughout the whole lung structure right down to the molecules [137].…”

“…Other structures include myosin filaments, actin filaments, cytoskeletal cross-linker molecules, cytosolic dense bodies, membrane adhesion plaques and cell-cell connections [55,185]. There is ample evidence for each of these candidates to be somehow involved in the response to external perturbation [168,174,[186][187][188][189][190][191].…”

Mechanotransduction, asthma and airway smooth muscle

“…To understand this behavior, other interactions than those between actin and myosin need to be considered. For instance, the binding interactions between the myosin proteins themselves within a thick filament can be overcome by excessive forces that lead to filament rupture, and the broken pieces can later be re-annealed [9]. It is conceivable to describe the myosin-myosin interaction too with a Huxleytype kinetic model, with rate constants that are dependent in force, filament length, and phosphorylation levels of certain regulatory proteins.…”

“…Several members of the dense plaque can directly connect to actin filaments (talin, vinculin, α-actinin) while others, such as focal adhesion kinase, are involved in downstream signaling via mitogenactivated protein (MAP) kinases and members of the Ras superfamily of small GTPases such as Rho, Rac, and Cdc42, [31]. On the one hand, these signaling events lead to altered focal adhesion dynamics and actin remodeling; on the other hand, they can alter the phosphorylation level of myosin light chain kinase and Rho-kinase, which in turn phosphorylate the myosin light chains and hence influence the force generation and myosin filament assembly [9,[32][33][34]. These processes are intertwined with second messenger signaling molecules including Ca2+/calmodulin, phosphatidylinositol, and cyclic adenosine monophosphate (cAMP) [12].…”

“…Such a force balance need not be static in the sense that the degree of airway constriction reaches a steadystate, and indeed, over the past decade numerous experimental and theoretical studies have shown that airway caliber is equilibrated dynamically rather than statically [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Indeed, the force-length curve of activated smooth muscle is constantly changing as the muscle adapts to its mechanical surroundings, such as the length to which it is stretched or the load against which it must contract.…”