title: Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins.
abstract: The Frank-Starling mechanism of the heart is due, in part, to modulation of myofilament Ca(2+) sensitivity by sarcomere length (SL) [length-dependent activation (LDA)]. The molecular mechanism(s) that underlie LDA are unknown. Recent evidence has implicated the giant protein titin in this cellular process, possibly by positioning the myosin head closer to actin. To clarify the role of titin strain in LDA, we isolated myocardium from either WT or homozygous mutant (HM) rats that express a giant splice isoform of titin, and subjected the muscles to stretch from 2.0 to 2.4 μm of SL. Upon stretch, HM compared with WT muscles displayed reduced passive force, twitch force, and myofilament LDA. Time-resolved small-angle X-ray diffraction measurements of WT twitching muscles during diastole revealed stretch-induced increases in the intensity of myosin (M2 and M6) and troponin (Tn3) reflections, as well as a reduction in cross-bridge radial spacing. Independent fluorescent probe analyses in relaxed permeabilized myocytes corroborated these findings. X-ray electron density reconstruction revealed increased mass/ordering in both thick and thin filaments. The SL-dependent changes in structure observed in WT myocardium were absent in HM myocardium. Overall, our results reveal a correlation between titin strain and the Frank-Starling mechanism. The molecular basis underlying this phenomenon appears not to involve interfilament spacing or movement of myosin toward actin but, rather, sarcomere stretch-induced simultaneous structural rearrangements within both thin and thick filaments that correlate with titin strain and myofilament LDA.
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153;
authors: Younss
authors: Y
authors: Ait-Mou
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153; Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL 60616;
authors: Karen
authors: K
authors: Hsu
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153;
authors: Gerrie P
authors: GP
authors: Farman
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153;
authors: Mohit
authors: M
authors: Kumar
authors: Department of Animal Sciences, Muscle Biology Laboratory, University of Wisconsin-Madison, Madison, WI 53706.
authors: Marion L
authors: ML
authors: Greaser
authors: Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL 60616;
authors: Thomas C
authors: TC
authors: Irving
authors: Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153; pdetombe@luc.edu.
authors: Pieter P
authors: PP
authors: de Tombe
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D064211:Connectin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D008955:Models, Cardiovascular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D009210:Myofibrils / Q000502:physiology; D009218:Myosins / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D053838:Scattering, Small Angle; D013314:Stress, Mechanical; D019209:Troponin C / Q000235:genetics / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D064211:Connectin; D050505:Mutant Proteins; D011994:Recombinant Proteins; D019209:Troponin C; C577295:Ttn protein, rat; D009218:Myosins
keywords: fluorescent probes; myofilament length-dependent activation; passive force; rat; small-angle X-ray diffraction