CoChat
Sign Up
Cited by 129Cardiomyopathy and Myosin StudiesProtein Structure and DynamicsCardiac electrophysiology and arrhythmias

Myosin filament-based regulation of the dynamics of contraction in heart muscle

Open access
Brunello, Elisabetta, Fusi, Luca, Ghisleni, Andrea, Park-Holohan, So-Jin, Ovejero, Jesus G., Narayanan, Theyencheri, Irving, Malcolm·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1920632117PMC PMC7149498
Open this paper in CoChat — free accountOpen PDF

Abstract

Significance: Cardiovascular disease continues to be the leading cause of death worldwide, and is frequently associated with heart failure. Efforts to develop better therapeutics for heart failure have been held back by limited understanding of the normal control of contraction on the timescale of the heartbeat. We used synchrotron X-ray diffraction to determine the dynamic structural changes in the myosin motors that drive contraction in the heart muscle, and show that myosin filament-based control mechanisms determine the time course and strength of contraction, allowing those mechanisms to be targeted for developing new therapies for heart disease.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1920632117

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 39

  1. [1]Bers D. M., Cardiac excitation-contraction coupling. Nature 415, 198– 205 (2002). 11805843
  2. [2]Reconditi M., Myosin filament activation in the heart is tuned to the mechanical task. Proc. Natl. Acad. Sci. U.S.A. 114, 3240– 3245 (2017). 28265101 PMC5373356
  3. [3]Solaro R. J., Multiplex kinase signaling modifies cardiac function at the level of sarcomeric proteins. J. Biol. Chem. 283, 26829– 26833 (2008). 18567577 PMC2556011
  4. [4]Stehle R., Iorga B., Kinetics of cardiac sarcomeric processes and rate-limiting steps in contraction and relaxation. J. Mol. Cell. Cardiol. 48, 843– 850 (2010). 20060002
  5. [5]Fusi L., Brunello E., Yan Z., Irving M., Thick filament mechano-sensing is a calcium-independent regulatory mechanism in skeletal muscle. Nat. Commun. 7, 13281 (2016). 27796302 PMC5095582
  6. [6]Irving M., Regulation of contraction by the thick filaments in skeletal muscle. Biophys. J. 113, 2579– 2594 (2017). 29262355 PMC5770512
  7. [7]Linari M., Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments. Nature 528, 276– 279 (2015). 26560032
  8. [8]Stewart M. A., Franks-Skiba K., Chen S., Cooke R., Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers. Proc. Natl. Acad. Sci. U.S.A. 107, 430– 435 (2010). 19966283 PMC2806748
  9. [9]Woodhead J. L., Atomic model of a myosin filament in the relaxed state. Nature 436, 1195– 1199 (2005). 16121187
  10. [10]Spudich J. A., Hypertrophic and dilated cardiomyopathy: Four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases. Biophys. J. 106, 1236– 1249 (2014). 24655499 PMC3985504
  11. [11]Toepfer C. N., Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci. Transl. Med. 11, eaat1199 (2019). 30674652 PMC7184965
  12. [12]Malik F. I., Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science 331, 1439– 1443 (2011). 21415352 PMC4090309
  13. [13]Luther P. K., Understanding the organisation and role of myosin binding protein C in normal striated muscle by comparison with MyBP-C knockout cardiac muscle. J. Mol. Biol. 384, 60– 72 (2008). 18817784 PMC2593797
  14. [14]Kampourakis T., Yan Z., Gautel M., Sun Y. B., Irving M., Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells. Proc. Natl. Acad. Sci. U.S.A. 111, 18763– 18768 (2014). 25512492 PMC4284530
  15. [15]Mun J. Y., Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. Proc. Natl. Acad. Sci. U.S.A. 111, 2170– 2175 (2014). 24477690 PMC3926057
  16. [16]Previs M. J., Beck Previs S., Gulick J., Robbins J., Warshaw D. M., Molecular mechanics of cardiac myosin-binding protein C in native thick filaments. Science 337, 1215– 1218 (2012). 22923435 PMC3561468
  17. [17]Zoghbi M. E., Woodhead J. L., Moss R. L., Craig R., Three-dimensional structure of vertebrate cardiac muscle myosin filaments. Proc. Natl. Acad. Sci. U.S.A. 105, 2386– 2390 (2008). 18252826 PMC2268146
  18. [18]Brunello E., Structural changes in the myosin filament and cross-bridges during active force development in single intact frog muscle fibres: Stiffness and X-ray diffraction measurements. J. Physiol. 577, 971– 984 (2006). 16990403 PMC1890380
  19. [19]Brunello E., Structural changes in myosin motors and filaments during relaxation of skeletal muscle. J. Physiol. 587, 4509– 4521 (2009). 19651765 PMC2766654
  20. [20]Huxley H. E., Brown W., The low-angle X-ray diagram of vertebrate striated muscle and its behaviour during contraction and rigor. J. Mol. Biol. 30, 383– 434 (1967). 5586931
  21. [21]Koubassova N. A., Bershitsky S. Y., Ferenczi M. A., Tsaturyan A. K., Direct modeling of X-ray diffraction pattern from contracting skeletal muscle. Biophys. J. 95, 2880– 2894 (2008). 18539638 PMC2527261
  22. [22]Pinzauti F., The force and stiffness of myosin motors in the isometric twitch of a cardiac trabecula and the effect of the extracellular calcium concentration. J. Physiol. 596, 2581– 2596 (2018). 29714038 PMC6023834
  23. [23]Woody M. S., Winkelmann D. A., Capitanio M., Ostap E. M., Goldman Y. E., Single molecule mechanics resolves the earliest events in force generation by cardiac myosin. eLife 8, e49266 (2019). 31526481 PMC6748826
  24. [24]Barclay C. J., Widén C., Efficiency of cross-bridges and mitochondria in mouse cardiac muscle. Adv. Exp. Med. Biol. 682, 267– 278 (2010). 20824531
  25. [25]Piazzesi G., Skeletal muscle performance determined by modulation of number of myosin motors rather than motor force or stroke size. Cell 131, 784– 795 (2007). 18022371
  26. [26]Malmqvist U. P., Aronshtam A., Lowey S., Cardiac myosin isoforms from different species have unique enzymatic and mechanical properties. Biochemistry 43, 15058– 15065 (2004). 15554713
  27. [27]Linari M., Interference fine structure and sarcomere length dependence of the axial X-ray pattern from active single muscle fibers. Proc. Natl. Acad. Sci. U.S.A. 97, 7226– 7231 (2000). 10860988 PMC16527
  28. [28]Reconditi M., Motion of myosin head domains during activation and force development in skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 108, 7236– 7240 (2011). 21482782 PMC3084075
  29. [29]Reconditi M., Recent improvements in small angle X-ray diffraction for the study of muscle physiology. Rep. Prog. Phys. 69, 2709– 2759 (2006). 19946470 PMC2783642
  30. [30]Labeit S., Kolmerer B., Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 270, 293– 296 (1995). 7569978
  31. [31]de Tombe P. P., Myofilament length dependent activation. J. Mol. Cell. Cardiol. 48, 851– 858 (2010). 20053351 PMC2854194
  32. [32]Ait-Mou Y., Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins. Proc. Natl. Acad. Sci. U.S.A. 113, 2306– 2311 (2016). 26858417 PMC4776536
  33. [33]Caremani M., Inotropic interventions do not change the resting state of myosin motors during cardiac diastole. J. Gen. Physiol. 151, 53– 65 (2019). 30510036 PMC6314382
  34. [34]Tong C. W., Stelzer J. E., Greaser M. L., Powers P. A., Moss R. L., Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ. Res. 103, 974– 982 (2008). 18802026 PMC2867079
  35. [35]Iskratsch T., Formin follows function: A muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance. J. Cell Biol. 191, 1159– 1172 (2010). 21149568 PMC3002041
  36. [36]Fusi L., Brunello E., Sevrieva I. R., Sun Y. B., Irving M., Structural dynamics of troponin during activation of skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 111, 4626– 4631 (2014). 24616505 PMC3970506
  37. [38]Narayanan T., A multipurpose instrument for time-resolved ultra-small-angle and coherent X-ray scattering. J. Appl. Cryst. 51, 1511– 1524 (2018). 30546286 PMC6276275
  38. [39]Fusi L., Huang Z., Irving M., The conformation of myosin heads in relaxed skeletal muscle: Implications for myosin-based regulation. Biophys. J. 109, 783– 792 (2015). 26287630 PMC4547144
  39. [40]Haselgrove J. C., X-ray evidence for conformational changes in the myosin filaments of vertebrate striated muscle. J. Mol. Biol. 92, 113– 143 (1975). 1080204

Cited by

Sorted by citations

Authors
Brunello, E., Fusi, L., Ghisleni, A., Park-Holohan, S.-J., Ovejero, J. G., Narayanan, T., & Irving, M.
Affiliations
  • King's College London (GB)
  • Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, King’s College London, SE1 1UL London, United Kingdom;
  • European Synchrotron Radiation Facility (FR)
Corresponding author
Brunello, Elisabetta
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-03-27
Volume
117
Issue
14
Pages
8177-8186
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1920632117
PMC
PMC7149498
OpenAlex
W3013015010
Cited by
129
References
0
Citations by year
2026: 12 · 2025: 18 · 2024: 18 · 2023: 27 · 2022: 17 · 2021: 30 · 2020: 7
FWCI
12.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Research Portal (King's College London) (submittedVersion, cc-by)
Funders
  • British Heart Foundation (FS/17/3/32604, PG/16/19/32072)
  • RCUK | Medical Research Council (MR/M026655/1)
  • Wellcome (210464/Z/18/Z)
  • Royal Society (210464/Z/18/Z)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
myosin filaments, cardiac muscle contraction, myosin binding protein C, stress sensing, actin-myosin interaction, relaxation, heart disease treatment
MeSH terms
Protein Domains, Myosin Binding Protein C, Animals, Carrier Proteins, Male, Myocardial Contraction, Myocardium, Myosins, Sarcomeres, X-Ray Diffraction, Synchrotrons, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review