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

Research output: Contribution to journalArticlepeer-review

Marco Linari, Elisabetta Brunello, Massimo Reconditi, Luca Fusi, Marco Caremani, Theyencheri Narayanan, Gabriella Piazzesi, Vincenzo Lombardi, Malcolm Irving

Original languageEnglish
Pages (from-to)276-279
Number of pages4
JournalNATURE
Volume528
Issue number7581
Early online date11 Nov 2015
DOIs
Accepted/In press21 Sep 2015
E-pub ahead of print11 Nov 2015
Published10 Dec 2015

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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.

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