title: Force generation by skeletal muscle is controlled by mechanosensing in myosin filaments.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Linari
authors.affiliation: Laboratory of Physiology, Department of Biology, Università di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Brunello
authors.affiliation: 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.
authors.forename: Massimo
authors.initials: M
authors.lastname: Reconditi
authors.affiliation: Randall Division and BHF Centre for Research Excellence, King's College London, London SE1 1UL, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Fusi
authors.affiliation: Laboratory of Physiology, Department of Biology, Università di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Caremani
authors.affiliation: European Synchrotron Radiation Facility, BP220, F-38043 Grenoble, France.
authors.forename: Theyencheri
authors.initials: T
authors.lastname: Narayanan
authors.affiliation: Laboratory of Physiology, Department of Biology, Università di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Piazzesi
authors.affiliation: Laboratory of Physiology, Department of Biology, Università di Firenze, Sesto Fiorentino, 50019 Florence, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lombardi
authors.affiliation: Randall Division and BHF Centre for Research Excellence, King's College London, London SE1 1UL, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Irving
mesh_terms: D000818:Animals; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D011896:Rana temporaria; D017356:Synchrotrons; D013997:Time Factors; D014961:X-Ray Diffraction
chemical_list: D009218:Myosins