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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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [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
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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 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.

Research Organization:
Loyola Univ. Chicago, Maywood, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States)
Contributing Organization:
Illinois Inst. of Technology, Chicago, IL (United States); Univ. of Wisconsin, Madison, WI (United States)
Grant/Contract Number:
AC02-06CH11357; HL075494; GM103622
OSTI ID:
1243123
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 8; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 114 works
Citation information provided by
Web of Science

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Cited By (32)

Titin mutations and muscle disease journal March 2019
Through thick and thin: dual regulation of insect flight muscle and cardiac muscle compared journal June 2019
Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes journal April 2017
Hypertrophic cardiomyopathy and the myosin mesa: viewing an old disease in a new light journal July 2017
Titin-truncating variants affect heart function in disease cohorts and the general population journal November 2016
Titin-mediated thick filament activation, through a mechanosensing mechanism, introduces sarcomere-length dependencies in mathematical models of rat trabecula and whole ventricle journal July 2017
Proposed mechanism for the length dependence of the force developed in maximally activated muscles journal February 2019
Myosin filament activation in the heart is tuned to the mechanical task journal March 2017
Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals journal February 2018
Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers journal August 2018
Recent applications of synchrotron radiation and neutrons in the study of soft matter journal February 2017
Regulatory light chain phosphorylation augments length-dependent contraction in PTU-treated rats journal December 2018
Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity journal April 2019
Inotropic interventions do not change the resting state of myosin motors during cardiac diastole journal December 2018
Sarcomere length–dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin journal December 2018
Getting into the thick (and thin) of it journal February 2019
Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model posted_content December 2019
The force and stiffness of myosin motors in the isometric twitch of a cardiac trabecula and the effect of the extracellular calcium concentration: Mechanical properties of cardiac myosin journal May 2018
End‐diastolic force pre‐activates cardiomyocytes and determines contractile force: role of titin and calcium journal July 2019
SarcOptiM for ImageJ: high-frequency online sarcomere length computing on stimulated cardiomyocytes journal August 2016
Does partial titin degradation affect sarcomere length nonuniformities and force in active and passive myofibrils? journal September 2018
Titin as a force-generating muscle protein under regulatory control journal May 2019
Increased Titin Compliance Reduced Length-Dependent Contraction and Slowed Cross-Bridge Kinetics in Skinned Myocardial Strips from Rbm20ΔRRM Mice journal July 2016
Distinct contributions of the thin and thick filaments to length-dependent activation in heart muscle journal February 2017
Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model journal February 2020
The Frank–Starling Law: a jigsaw of titin proportions journal June 2017
Titin-mediated thick filament activation stabilizes myofibrils on the descending limb of their force–length relationship journal July 2018
Elastic domains of giant proteins in striated muscle: Modeling compliance with rulers journal April 2019
Which way to grow? Force over time may be the heart’s Dao de jing journal October 2016
The Effects of Mechanical Preload on Transmural Differences in Mechano-Calcium-Electric Feedback in Single Cardiomyocytes: Experiments and Mathematical Models journal March 2020
Stretch-Induced Biased Signaling in Angiotensin II Type 1 and Apelin Receptors for the Mediation of Cardiac Contractility and Hypertrophy journal March 2020
Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle journal September 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
59 BASIC BIOLOGICAL SCIENCES
myofilament length-dependent activation
small-angle X-ray diffraction
rat
passive force
fluorescent probes