title: Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle.
abstract: Actin cytoskeletal remodeling is an important mechanism of airway smooth muscle (ASM) contraction. We tested the hypothesis that mechanical strain modulates the cholinergic receptor-mediated cytoskeletal recruitment of actin-binding and integrin-binding proteins in intact airway smooth muscle, thereby regulating the mechanical energetics of airway smooth muscle. We found that the carbachol-stimulated cytoskeletal recruitment of actin-related protein-3 (Arp3), metavinculin, and talin were up-regulated at short muscle lengths and down-regulated at long muscle lengths, suggesting that the actin cytoskeleton--integrin complex becomes enriched in cross-linked and branched actin filaments in shortened ASM. The mechanical energy output/input ratio during sinusoidal length oscillation was dependent on muscle length, oscillatory amplitude, and cholinergic activation. The enhancing effect of cholinergic stimulation on mechanical energy output/input ratio at short and long muscle lengths may be explained by the length-dependent modulation of cytoskeletal recruitment and crossbridge cycling, respectively. We postulate that ASM functions as a hybrid biomaterial, capable of switching between operating as a cytoskeleton-based mechanical energy store at short muscle lengths to operating as an actomyosin-powered mechanical energy generator at long muscle lengths. This postulate predicts that targeting the signaling molecules involved in cytoskeletal recruitment may provide a novel approach to dilating collapsed airways in obstructive airway disease.
authors: Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island 02912, USA.
authors: Hak Rim
authors: HR
authors: Kim
authors: Katrina
authors: K
authors: Liu
authors: Thomas J
authors: TJ
authors: Roberts
authors: Chi-Ming
authors: CM
authors: Hai
mesh_terms: D051378:Actin-Related Protein 3 / Q000378:metabolism; D000199:Actins / Q000737:chemistry; D000818:Animals; D016084:Bronchoconstriction; D002217:Carbachol / Q000494:pharmacology; D002417:Cattle; D003432:Cross-Linking Reagents / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D009991:Oscillometry / Q000379:methods; D010766:Phosphorylation; D029424:Pulmonary Disease, Chronic Obstructive / Q000628:therapy; D013314:Stress, Mechanical; D016608:Talin / Q000378:metabolism; D014132:Trachea / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
chemical_list: D051378:Actin-Related Protein 3; D000199:Actins; D003432:Cross-Linking Reagents; D016608:Talin; C103334:metavinculin; D016596:Vinculin; D002217:Carbachol