Biphasic force response to iso-velocity stretch in airway smooth muscle

Abstract

Airway smooth muscle (ASM) in vivo is constantly subjected to oscillatory strain due to tidal breathing and deep inspirations. ASM contractility is known to be adversely affected by strains, especially those of large amplitudes. Based on the cross-bridge model of contraction, it is likely that strain impairs force generation by disrupting actomyosin cross-bridge interaction. There is also evidence that strain modulates muscle stiffness and force through induction of cytoskeletal remodeling. However, the molecular mechanism by which strain alters smooth muscle function is not entirely clear. Here, we examine the response of ASM to iso-velocity stretches to probe the components within the muscle preparation that give rise to different features in the force response. We found in ASM that force response to a ramp stretch showed a biphasic feature, with the initial phase associated with greater muscle stiffness compared with that in the later phase, and that the transition between the phases occurred at a critical strain of ∼3.3%. Only strains with amplitudes greater than the critical strain could lead to reduction in force and stiffness of the muscle in the subsequent stretches. The initial-phase stiffness was found to be linearly related to the degree of muscle activation, suggesting that the stiffness stems mainly from attached cross bridges. Both phases were affected by the degree of muscle activation and by inhibitors of myosin light-chain kinase, PKC, and Rho-kinase. Different responses due to different interventions suggest that cross-bridge and cytoskeletal stiffness is regulated differently by the kinases.

The impact of low-frequency, low-force cyclic stretching of human bronchi on airway responsiveness

“…The low-force strain was enough to increase the stiffness of the bronchial ring during our dynamic and cyclic stretching, as suggested by Norris et al. The latter researchers described a biphasic ASM response to an isovelocity stretch; the first phase concerned the actomyosin interaction and the second phase was dependent on the ASM’s level of activation [5]. The absence of a pre-inflammatory bronchial state is another possible explanation for the absence of a rise in levels of mediators.…”

“…Indeed, the repetitive inflation-deflation caused by positive-pressure ventilation may provoke a specific response by the ASM, which is known to be adversely affected by mechanical strain (especially high-amplitude strain) [3, 4]. Based on the cross-bridge model of contraction, mechanical strain impairs force generation by disrupting actomyosin cross-bridge interactions [5]. There is also evidence to suggest that strain modulates muscle stiffness and force by inducting cytoskeletal remodeling - even at low levels of strain (greater or equal to a lengthening of 3%) [5].…”

“…Based on the cross-bridge model of contraction, mechanical strain impairs force generation by disrupting actomyosin cross-bridge interactions [5]. There is also evidence to suggest that strain modulates muscle stiffness and force by inducting cytoskeletal remodeling - even at low levels of strain (greater or equal to a lengthening of 3%) [5]. Length adaptation may also contribute to airway hyperresponsiveness (AHR) in asthma [6].…”

The newborn rat gastric emptying rate is volume and not developmentally dependent

“…As judged by the Western blot findings and the Y27632 inhibitory effect, the present data demonstrate that wall strain‐dependent changes regulate the fundic muscle contraction potential via the ROCK‐2 signaling pathway. Stretch‐induced ROCK activation was reported in cardiomyocytes, alveolar epithelia, vascular, airway, and bladder tissues . The factors regulating this signaling pathway are not completely understood.…”

“…Stretch-induced ROCK activation was reported in cardiomyocytes, alveolar epithelia, vascular, airway, and bladder tissues. 5,[24][25][26][27][28] The factors regulating this signaling pathway are not completely understood. Caveolae-dependent ERK translocation, 24 changes in p38 and HSP27 phosphorylation, 26 as well as, c-Jun NH2 terminal kinase activation 27 have been reported to play a role in this process.…”