Journal Article

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

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

2015

Overview

It is widely accepted that contraction of skeletal muscle and the heart involves structural changes in actin-containing thin filaments to allow binding of myosin motors from neighbouring thick filaments, thus driving filament sliding; here, X-ray diffraction of single skeletal muscle cells reveals that this thin-filament mechanism can regulate muscle contraction against low load, but high-load contraction requires a second permissive step involving a structural change in the thick filament. A new take on muscle contraction It is thought that for the contraction of skeletal muscle and the heart, structural changes in the actin-containing thin filaments allow the binding of filaments to myosin motors from the neighbouring thick filaments that drives filament sliding. Yet this decades-old concept cannot account for the fact that, in resting muscle, myosin motors cannot bind to the thin filaments. Vincenzo Lombardi and colleagues test the hypothesis that a second permissive step for muscle shortening involves a structural change in the thick filament. Their analysis of single skeletal muscle cells reveals that the accepted thin-filament mechanism, involving a small fraction of constitutively 'ON' myosin motors, can regulate muscle contraction against low load. However, force generation against high load indeed requires change in the structure of the thick filaments, which under low load form an 'OFF' structure. 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 1 , 2 , 3 . 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 2 , 4 , 5 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/811 / 631/57/343/1667 / 631/80/128 / Animals / Biomechanics / Humanities and Social Sciences / letter / Load / Male / Mechanotransduction, Cellular - physiology / Molecular biology / multidisciplinary / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / Myosin / Myosins - metabolism / Physiological aspects / Rana temporaria / Science / Synchrotrons / Time Factors / X-Ray Diffraction