Abstract

Time-resolved X-ray diffraction from isolated fast-twitch muscles of the mouse was used to show how structural changes in the myosin-containing thick filaments contribute to the regulation of muscle contraction, extending the previous focus on regulation by the actin-containing thin filaments. This study shows that muscle activation involves the following sequence of structural changes: thin filament activation, disruption of the helical array of myosin motors characteristic of resting muscle, release of myosin motor domains from the folded conformation on the filament backbone, and actin attachment. Physiological force generation in the 'twitch' response of skeletal muscle to single action potential stimulation is limited by incomplete activation of the thick filament and the rapid inactivation of both filaments. Muscle relaxation after repetitive stimulation is accompanied by complete recovery of the folded motor conformation on the filament backbone but incomplete reformation of the helical array, revealing a structural basis for post-tetanic potentiation in isolated muscle.

Data availability

All source data for data analysed in this study are provided for figures 1 to 6.

Article and author information

Author details

  1. Cameron Hill

    Randall Centre for Cell & Molecular Biophysics, King's College London, London, United Kingdom
    For correspondence
    cameron.hill@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0815-5109
  2. Elisabetta Brunello

    Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3167-4828
  3. Luca Fusi

    Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3992-0114
  4. Jesús G Ovejero

    Randall Centre for Cell & Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3774-6589
  5. Malcolm Irving

    Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

Funding

Medical Research Council (MR/R01700X/1)

  • Cameron Hill
  • Malcolm Irving

Diamond Light Source (SM21316-1)

  • Cameron Hill
  • Elisabetta Brunello
  • Luca Fusi
  • Jesús G Ovejero
  • Malcolm Irving

British Heart Foundation Intermediate Basic Science Research Fellowship (FS/17/3/32604)

  • Elisabetta Brunello
  • Jesús G Ovejero

Sir Henry Dale Fellowship, Wellcome Trust and The Royal Society (210464/Z/18/Z)

  • Luca Fusi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animals were housed and maintained following the ARRIVE guidelines (Kilkenny et al., 2010; PLOS Biology, 8:e1000412). Animals were sacrificed via cervical dislocation in compliance with the UK Home Office Animals (Scientific Procedures) Act 1986, Schedule 1.

Copyright

© 2021, Hill et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,185
    views
  • 400
    downloads
  • 27
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Cameron Hill
  2. Elisabetta Brunello
  3. Luca Fusi
  4. Jesús G Ovejero
  5. Malcolm Irving
(2021)
Myosin-based regulation of twitch and tetanic contractions in mammalian skeletal muscle
eLife 10:e68211.
https://doi.org/10.7554/eLife.68211

Share this article

https://doi.org/10.7554/eLife.68211

Further reading

    1. Cell Biology
    2. Physics of Living Systems
    Marta Urbanska, Yan Ge ... Jochen Guck
    Research Article

    Cell mechanical properties determine many physiological functions, such as cell fate specification, migration, or circulation through vasculature. Identifying factors that govern the mechanical properties is therefore a subject of great interest. Here, we present a mechanomics approach for establishing links between single-cell mechanical phenotype changes and the genes involved in driving them. We combine mechanical characterization of cells across a variety of mouse and human systems with machine learning-based discriminative network analysis of associated transcriptomic profiles to infer a conserved network module of five genes with putative roles in cell mechanics regulation. We validate in silico that the identified gene markers are universal, trustworthy, and specific to the mechanical phenotype across the studied mouse and human systems, and demonstrate experimentally that a selected target, CAV1, changes the mechanical phenotype of cells accordingly when silenced or overexpressed. Our data-driven approach paves the way toward engineering cell mechanical properties on demand to explore their impact on physiological and pathological cell functions.

    1. Physics of Living Systems
    M Julia Maristany, Anne Aguirre Gonzalez ... Jerelle A Joseph
    Research Article

    Proteins containing prion-like low complexity domains (PLDs) are common drivers of the formation of biomolecular condensates and are prone to misregulation due to amino acid mutations. Here, we exploit the accuracy of our residue-resolution coarse-grained model, Mpipi, to quantify the impact of amino acid mutations on the stability of 140 PLD mutants from six proteins (hnRNPA1, TDP43, FUS, EWSR1, RBM14, and TIA1). Our simulations reveal the existence of scaling laws that quantify the range of change in the critical solution temperature of PLDs as a function of the number and type of amino acid sequence mutations. These rules are consistent with the physicochemical properties of the mutations and extend across the entire family tested, suggesting that scaling laws can be used as tools to predict changes in the stability of PLD condensates. Our work offers a quantitative lens into how the emergent behavior of PLD solutions vary in response to physicochemical changes of single PLD molecules.