Friction in airway smooth muscle: mechanism, latch, and implications in asthma

Abstract

In muscle, active force and stiffness reflect numbers of actin-myosin interactions and shortening velocity reflects their turnover rates, but the molecular basis of mechanical friction is somewhat less clear. To better characterize molecular mechanisms that govern mechanical friction, we measured the rate of mechanical energy dissipation and the rate of actomyosin ATP utilization simultaneously in activated canine airway smooth muscle subjected to small periodic stretches as occur in breathing. The amplitude of the frictional stress is proportional to eta E, where E is the tissue stiffness defined by the slope of the resulting force vs. displacement loop and eta is the hysteresivity defined by the fatness of that loop. From contractile stimulus onset, the time course of frictional stress amplitude followed a biphasic pattern that tracked that of the rate of actomyosin ATP consumption. The time course of hysteresivity, however, followed a different biphasic pattern that tracked that of shortening velocity. Taken together with an analysis of mechanical energy storage and dissipation in the cross-bridge cycle, these results indicate, first, that like shortening velocity and the rate of actomyosin ATP utilization, mechanical friction in airway smooth muscle is also governed by the rate of cross-bridge cycling; second, that changes in cycling rate associated with conversion of rapidly cycling cross bridges to slowly cycling latch bridges can be assessed from changes of hysteresivity of the force vs. displacement loop; and third, that steady-state force maintenance (latch) is a low-friction contractile state. This last finding may account for the unique inability of asthmatic patients to reverse spontaneous airways obstruction with a deep inspiration.

Mechanotransduction, asthma and airway smooth muscle

“…Accordingly, a brief, transient force increase leads to a long-lasting lengthening of the muscle, and a brief, transient length increase leads to a long-lasting force reduction and softening of the muscle. These model predictions have been qualitatively confirmed in numerous smooth muscle studies [2][3][4][5]8].…”

“…This so-called latch state of myosin, named so because the interactions with actin are greatly slowed down, can account for certain properties of smooth muscle after stimulation, such as a decrease in ATP-utilization and velocity of shortening over time [2,8]. But even without the latch state, the binding interaction between actin and myosin proteins, with no other regulatory processes involved, exhibit an extraordinarily complex mechanical sensitivity [8].…”

“…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.…”

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

“…dynamics (i.e., cycling rate) likely plays a role. Fredbergs's laboratory and our work (Figures 2 and 3) have demonstrated increased hysteresivity with larger force fluctuations (1)(2)(3). Hysteresivity is a reflection of actomyosin crossbridge cycling.…”

“…Here we have reviewed a number of possible theories for this difference. We have presented published data that strongly implicate FFIR as a key component of this breathing effect (1)(2)(3)(4). Furthermore, we have suggested, based on our previous work, that actin filament length is a major determinant of FFIR (1).…”