Titin-mediated thick filament activation stabilizes myofibrils on the descending limb of their force–length relationship

Figures

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  Fig. 1. Sketch of a (non-activated) sarcomere consisting of 2 non-uniform half-sarcomeres. Although actin–myosin overlap of the left half-sarcomere is greater, its fraction of myosin motors in the on-state (green) is smaller due to the smaller extension of titin and therefore smaller passive force compared to the half-sarcomere on the right.

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  Fig. 2. The classical three-state cross-bridge working cycle augmented by a super-relaxed state.

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  Fig. 3. Sketch of the sarcomere model. The motion of the M-line is governed by active forces (Factive1,2), passive forces (Fpassive1,2), external viscous force (Fdrag), and external forces (Fext).

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  Fig. 4. Differences in half-sarcomere lengths for an isometric contraction (first second) and subsequent stretching (Seconds 1–3). In the mechanosensing model (MS, red line), the long half-sarcomere is stable for the first 100 ms, whereas in the classical model (classical, black line), the long half-sarcomere is immediately being stretched. Although differences in half-sarcomere lengths increase over time, the differences are significantly smaller in the MS than in the classical model.

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  Fig. 5. Differences in the active half-sarcomere forces during sarcomere stretching. Forces are normalized to the forces of the short half-sarcomere. Differences in active half-sarcomere force are significantly smaller in the mechanosensing model (MS, red line) than in the classical cross-bridge model (classical, black line).

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  Fig. 6. Half-sarcomere lengths of the short half-sarcomere before calcium-mediated thin filament activation (1), after 1 s of-quasi-isometric contraction (2), and after 2 s of active stretching (3) of 25 non-uniform sarcomeres. Although the classical cross-bridge model (A) always predicts shortening during the quasi-isometric contraction, half-sarcomere lengths remain stable in the mechanosensing model. Furthermore, the mechanosensing model (B) predicts lengthening of the half-sarcomeres or all levels of length non-uniformities. This is in contrast to the classical cross-bridge model, which predicts shortening of half-sarcomeres for sarcomeres with half-sarcomere length differences greater than 250 nm before activation.