Key result
Imposing 10-ms unloaded shortening at the start of stimulation delayed myosin filament activation in mouse muscle, showing stress is the major mechanism of activation.
Why the study?
Previous findings in amphibian muscle suggested myosin filaments are activated by mechanical stress, motivating an investigation with improved signal-to-noise ratio in mammalian muscle.
This preclinical study demonstrates that myosin filaments in mouse fast-twitch muscle are predominantly activated by mechanical stress, with a minor component of activation occurring independently at zero load.
Preclinical mouse data warrant clinical caution; leaves open translation to human muscle mechanics.
Myosin motors in resting muscle are inactivated by folding against the backbone of the myosin filament in an ordered helical array and must be released from that conformation to engage in force generation. Time-resolved X-ray diffraction from single fibres of amphibian muscle showed that myosin filament activation could be inhibited by imposing unloaded shortening at the start of stimulation, suggesting that filaments were activated by mechanical stress. Here we improved the signal-to-noise ratio of that approach using whole extensor digitorum longus muscles of the mouse contracting tetanically at 28°C. Changes in X-ray signals associated with myosin filament activation, including the decrease in the first-order myosin layer line associated with the helical motor array, increase in the spacing of a myosin-based reflection associated with packing of myosin tails in the filament backbone, and increase in the ratio of the 1,1 and 1,0 equatorial reflections associated with movement of motors away from the backbone, were delayed by imposing 10-ms unloaded shortening at the start of stimulation. These results show that myosin filaments are predominantly activated by filament stress, as in amphibian muscle. However, a small component of filament activation at zero load was detected, implying an independent mechanism of partial filament activation. X-ray interference measurements indicated a switch-like change in myosin motor conformation at the start of force development, accompanied by transient disordering of motors in the regions of the myosin filament near its midpoint, suggesting that filament zonal dynamics also play a role in its activation. KEY POINTS: Activation of myosin filaments in extensor digitorum longus muscles of the mouse is delayed by imposing rapid shortening from the start of stimulation. Stress is the major mechanism of myosin filament activation in these muscles, but there is a small component of filament activation during electrical stimulation at zero stress. Myosin motors switch rapidly from the folded inhibited conformation to the actin-attached force-generating conformation early in force development.
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Hill et al. (2022) studied this question. 10-ms unloaded shortening at the start of stimulation was evaluated on Changes in X-ray signals associated with myosin filament activation. Imposing 10-ms unloaded shortening at the start of stimulation delayed myosin filament activation in mouse muscle, showing stress is the major mechanism of activation.
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