Abstract
Time-resolved X-ray diffraction of isolated fast-twitch muscles of mice was used to show how structural changes in the myosin-containing thick filaments contribute to the regulation of muscle contraction, extending the previous focus on regulation by the actin-containing thin filaments. This study shows that muscle activation involves the following sequence of structural changes: thin filament activation, disruption of the helical array of myosin motors characteristic of resting muscle, release of myosin motor domains from the folded conformation on the filament backbone, and actin attachment. Physiological force generation in the 'twitch' response of skeletal muscle to single action potential stimulation is limited by incomplete activation of the thick filament and the rapid inactivation of both filaments. Muscle relaxation after repetitive stimulation is accompanied by a complete recovery of the folded motor conformation on the filament backbone but by incomplete reformation of the helical array, revealing a structural basis for post-tetanic potentiation in isolated muscles.
Highlights
The unitary contractile response of skeletal muscle to an action potential in the muscle cell membrane—the twitch—is triggered by a transient increase in intracellular calcium concentration ([Ca2+]i), leading to calcium binding to troponin in the actin-containing thin filaments
The results presented above allow structural changes in the thick filaments and myosin head or motor domains to be followed with 5 ms time resolution during activation and relaxation of intact mouse extensor digitorum longus (EDL) muscle
The functional significance of these structural changes is clearer for tetanus than for twitch, in which activation and relaxation are clearly separated by a period of steady-state sarcomere-isometric contraction in which the thin filaments are maximally activated by calcium
Summary
The unitary contractile response of skeletal muscle to an action potential in the muscle cell membrane—the twitch—is triggered by a transient increase in intracellular calcium concentration ([Ca2+]i), leading to calcium binding to troponin in the actin-containing thin filaments. The duration of the [Ca2+]i transient is much briefer than the mechanical response in the twitch, but peak [Ca2+]i is an order of magnitude larger than the dissociation constant of the Ca2+ regulatory sites on troponin, which become fully occupied with a delay of less than 1 ms after peak [Ca2+]i in mammalian muscle at 28 ̊C (Baylor and Hollingworth, 2003). Tetanic stimulation increases the duration, but not the peak amplitude, of the [Ca2+]i transient or the peak occupancy of the Ca2+ regulatory sites on troponin compared to that in the twitch (Baylor and Hollingworth, 2003) It follows that the [Ca2+]i transient provides a ‘start’ signal for contraction but does not control either the amplitude or the time course of the twitch in skeletal muscle
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