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Title: Titin strain contributes to the Frank–Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins

The Frank–Starling mechanism of the heart is due, in part, to modulation of myofilament Ca2+ 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 thismore » 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.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [1]
  1. Loyola Univ. Chicago, Maywood, IL (United States). Dept. of Cell and Molecular Physiology
  2. Loyola Univ. Chicago, Maywood, IL (United States). Dept. of Cell and Molecular Physiology; Illinois Inst. of Technology, Chicago, IL (United States). Dept. of Biological and Chemical Sciences
  3. Univ. of Wisconsin, Madison, WI (United States). Dept. of Animal Sciences. Muscle Biology Lab.
  4. Illinois Inst. of Technology, Chicago, IL (United States). Dept. of Biological and Chemical Sciences
Publication Date:
OSTI Identifier:
1243123
Grant/Contract Number:
AC02-06CH11357; HL075494; GM103622
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 8; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Loyola Univ. Chicago, Maywood, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States)
Contributing Orgs:
Illinois Inst. of Technology, Chicago, IL (United States); Univ. of Wisconsin, Madison, WI (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; myofilament length-dependent activation; small-angle X-ray diffraction; rat; passive force; fluorescent probes