title: 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.
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Norris
authors.affiliation: Department of Environmental Health, Harvard University, Boston, Massachusetts; Department of Physiology and Pharmacology, University of Calgary, Alberta, Canada;
authors.forename: Bo
authors.initials: B
authors.lastname: Lan
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pascoe
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Swyngedouw
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; and Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada chun.seow@hli.ubc.ca.
authors.forename: Chun Y
authors.initials: CY
authors.lastname: Seow
mesh_terms: D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology*; D053580:Muscle Strength / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015656:Respiratory Mechanics / Q000502:physiology*; D012137:Respiratory System; D012756:Sheep; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D054460:rho-Associated Kinases; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase
keywords: GF109203x; H1152; ML-7; critical strain; muscle mechanics; stiffness