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Mechanism of force generation by myosin heads in skeletal muscle

Nature volume 415, pages 659–662 (2002)Cite this article

Abstract

Muscles generate force and shortening in a cyclical interaction between the myosin head domains projecting from the myosin filaments and the adjacent actin filaments. Although many features of the dynamic performance of muscle are determined by the rates of attachment and detachment of myosin and actin1, the primary event in force generation is thought to be a conformational change or ‘working stroke’ in the actin-bound myosin head2,3,4,5,6,7,8. According to this hypothesis, the working stroke is much faster than attachment or detachment, but can be observed directly in the rapid force transients that follow step displacement of the filaments3. Although many studies of the mechanism of muscle contraction9,10,11,12,13 have been based on this hypothesis, the alternative view—that the fast force transients are caused by fast components of attachment and detachment14,15,16,17 —has not been excluded definitively. Here we show that measurements of the axial motions of the myosin heads at ångström resolution by a new X-ray interference technique18 rule out the rapid attachment/detachment hypothesis, and provide compelling support for the working stroke model of force generation.

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Figure 1: Changes in interference fine structure of the M3 X-ray reflection produced by rapid shortening.
Figure 2: Relative intensity and spacings of the higher (HA) and lower (LA) angle peaks of the M3 reflection.
Figure 3: Axial motions and spacings of myosin heads.

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References

  1. Huxley, A. F. Muscle structure and theories of contraction. Prog. Biophys. Biophys. Chem. 7, 255–318 (1957).

    Article  CAS  Google Scholar 

  2. Huxley, H. E. The mechanism of muscle contraction. Science 164, 1356–1366 (1969).

    Article  ADS  CAS  Google Scholar 

  3. Huxley, A. F. & Simmons, R. M. Proposed mechanism of force generation in striated muscle. Nature 233, 533–538 (1971).

    Article  ADS  CAS  Google Scholar 

  4. Huxley, A. F. Muscular contraction (review lecture). J. Physiol. (Lond.) 243, 1–43 (1974).

    Article  CAS  Google Scholar 

  5. Rayment, I. et al. Three-dimensional structure of myosin subfragment-1: a molecular motor. Science 261, 50–58 (1993).

    Article  ADS  CAS  Google Scholar 

  6. Rayment, I. et al. Structure of the actin–myosin complex and its implications for muscle contraction. Science 261, 58–65 (1993).

    Article  ADS  CAS  Google Scholar 

  7. Dominguez, R., Freyzon, Y., Trybus, K. M. & Cohen, C. Crystal structure of a vertebrate smooth muscle myosin motor domain and its complex with the essential light chain: visualisation of the pre-power stroke state. Cell 94, 559–571 (1998).

    Article  CAS  Google Scholar 

  8. Geeves, M. A. & Holmes, K. C. Structural mechanism of muscle contraction. Annu. Rev. Biochem. 68, 687–728 (1999).

    Article  CAS  Google Scholar 

  9. Huxley, H. E. et al. Changes in the X-ray reflections from contracting muscle during rapid mechanical transients and their structural implications. J. Mol. Biol. 169, 469–506 (1983).

    Article  CAS  Google Scholar 

  10. Irving, M., Lombardi, V., Piazzesi, G. & Ferenczi, M. A. Myosin head movements are synchronous with the elementary force-generating process in muscle. Nature 357, 156–158 (1992).

    Article  ADS  CAS  Google Scholar 

  11. Lombardi, V., Piazzesi, G. & Linari, M. Rapid regeneration of the actin–myosin power stroke in contracting muscle. Nature 355, 638–641 (1992).

    Article  ADS  CAS  Google Scholar 

  12. Irving, M. et al. Conformation of the myosin motor during force generation in skeletal muscle. Nature Struct. Biol. 7, 482–485 (2000).

    Article  CAS  Google Scholar 

  13. Corrie, J. E. T. et al. Dynamic measurement of myosin light-chain domain tilt and twist in muscle contraction. Nature 400, 425–430 (1999).

    Article  ADS  CAS  Google Scholar 

  14. Podolsky, R. J. & Nolan, A. C. Muscle contraction transients, cross-bridge kinetics, and the Fenn effect. Cold Spring Harb. Symp. Quant. Biol. 37, 661–668 (1973).

    Article  CAS  Google Scholar 

  15. Brenner, B. Rapid dissociation and reassociation of actomyosin cross-bridges during force generation: a newly observed facet of cross-bridge action in muscle. Proc. Natl Acad. Sci. USA 88, 10490–10494 (1991).

    Article  ADS  CAS  Google Scholar 

  16. Kitamura, K., Tokunaga, M., Iwane, A. H. & Yanagida, T. A single myosin head moves along an actin filament with regular steps of 5.3 nanometres. Nature 397, 129–134 (1999).

    Article  ADS  CAS  Google Scholar 

  17. Howard, J. Mechanics of Motor Proteins and the Cytoskeleton (Sinauer, Sunderland, MA, 2001).

    Google Scholar 

  18. Linari, M. et al. Interference fine structure and sarcomere length dependence of the axial X-ray pattern from active single muscle fibres. Proc. Natl Acad. Sci. USA 97, 7226–7231 (2000).

    Article  ADS  CAS  Google Scholar 

  19. Ford, L. E., Huxley, A. F. & Simmons, R. M. Tension responses to sudden length change in stimulated frog muscle fibres near slack length. J. Physiol. (Lond.) 269, 441–515 (1977).

    Article  CAS  Google Scholar 

  20. Dobbie, I. et al. Elastic bending and active tilting of myosin heads during muscle contraction. Nature 396, 383–387 (1998).

    Article  ADS  CAS  Google Scholar 

  21. Linari, M. et al. The stiffness of skeletal muscle in isometric contraction and rigor: the fraction of myosin heads bound to actin. Biophys. J. 74, 2459–2473 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Piazzesi, G. et al. Changes in conformation of myosin heads during the development of isometric contraction and rapid shortening in single frog muscle fibres. J. Physiol. (Lond.) 514, 305–312 (1999).

    Article  CAS  Google Scholar 

  23. Lombardi, V. & Piazzesi, G. The contractile response during steady lengthening of stimulated frog muscle fibres. J. Physiol. (Lond.) 431, 141–171 (1990).

    Article  CAS  Google Scholar 

  24. Huxley, A. F., Lombardi, V. & Peachey, L. D. A system for fast recording of longitudinal displacement of a striated muscle fibre. J. Physiol. (Lond.) 317, 12P–13P (1981).

    Google Scholar 

  25. Boesecke, P., Diat, O. & Rasmussen, B. High-brilliance beamline at the European Synchrotron Radiation Facility. Rev. Sci. Instrum. 66, 1636–1638 (1995).

    Article  ADS  Google Scholar 

  26. Haselgrove, J. C. X-ray evidence for conformational changes in the myosin filaments of vertebrate striated muscle. J. Mol. Biol. 92, 113–143 (1975).

    Article  CAS  Google Scholar 

  27. Sjöström M. & Squire, J. M. Fine structure of the A band in cryosections: the structure of the A-band of human skeletal muscle fibres from ultrathin cryosections negatively stained. J. Mol. Biol. 109, 49–68 (1977).

    Article  Google Scholar 

  28. Craig, R. Structure of A-segments from frog and rabbit skeletal muscle. J. Mol. Biol. 109, 69–81 (1977).

    Article  CAS  Google Scholar 

  29. Thorson, J. W. & White, D. C. S. Distributed representations for actin-myosin interaction in the oscillatory contraction of muscle. Biophys. J. 9, 360–390 (1969).

    Article  ADS  CAS  Google Scholar 

  30. Ford, L. E., Huxley, A. F. & Simmons, R. M. The relation between stiffness and filament overlap in stimulated frog muscle fibres. J. Physiol. (Lond) 311, 219–249 (1981).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Medical Research Council, Consiglio Nazionale della Ricerche (CNR), Ministero dell'Istruzione, dell'Università e della Ricerca (MURST), Telethon (Italy), EMBL, EU and ESRF. We thank A. F. Huxley for comments, J. Gorini, A. Aiazzi and M. Dolfi for mechanical and electronics support.

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Authors and Affiliations

  1. Università di Firenze, Viale G.B. Morgagni 63, Firenze, I-50134, Italy

    Gabriella Piazzesi, Massimo Reconditi, Marco Linari, Leonardo Lucii & Vincenzo Lombardi

  2. Randall Centre, School of Biomedical Sciences, King's College London, London, SE1 1UL, UK

    Yin-Biao Sun & Malcolm Irving

  3. European Synchrotron Radiation Facility, Grenoble Cedex, F-38043, France

    Theyencheri Narayanan & Peter Boesecke

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  1. Gabriella Piazzesi
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Correspondence to Malcolm Irving.

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Piazzesi, G., Reconditi, M., Linari, M. et al. Mechanism of force generation by myosin heads in skeletal muscle. Nature 415, 659–662 (2002). https://doi.org/10.1038/415659a

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