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Nature. 2015 Dec 10;528(7581):276-9. doi: 10.1038/nature15727. Epub 2015 Nov 11.

Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments.

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Laboratory of Physiology, Department of Biology, Università di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia, UdR Firenze, Sesto Fiorentino, 50019 Florence, Italy.
Randall Division and BHF Centre for Research Excellence, King's College London, London SE1 1UL, UK.
European Synchrotron Radiation Facility, BP220, F-38043 Grenoble, France.


Contraction of both skeletal muscle and the heart is thought to be controlled by a calcium-dependent structural change in the actin-containing thin filaments, which permits the binding of myosin motors from the neighbouring thick filaments to drive filament sliding. Here we show by synchrotron small-angle X-ray diffraction of frog (Rana temporaria) single skeletal muscle cells that, although the well-known thin-filament mechanism is sufficient for regulation of muscle shortening against low load, force generation against high load requires a second permissive step linked to a change in the structure of the thick filament. The resting (switched 'OFF') structure of the thick filament is characterized by helical tracks of myosin motors on the filament surface and a short backbone periodicity. This OFF structure is almost completely preserved during low-load shortening, which is driven by a small fraction of constitutively active (switched 'ON') myosin motors outside thick-filament control. At higher load, these motors generate sufficient thick-filament stress to trigger the transition to its long-periodicity ON structure, unlocking the major population of motors required for high-load contraction. This concept of the thick filament as a regulatory mechanosensor provides a novel explanation for the dynamic and energetic properties of skeletal muscle. A similar mechanism probably operates in the heart.

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