Reduced preload increases Mechanical Control (strain-rate dependence) of Relaxation by modifying myosin kinetics

Figures

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  Fig. 1.. Example experimental data. A&B) Tension, Length normalized to Lo, and strain rate for a muscle at Lo (Panel A, purple) and a muscle reduced in length (Panel B, green) to 0.96 Lo of the trabeculae length (0.975 Lo of pin-to-pin length). An isometric trace (dark solid), a load-clamp with no relengthening (solid line), and a load-clamp trace fully relengthened (dashed line) are shown. C) Image of the cardiac trabeculae at Lo and schematic of mounting. Trabeculae length was used unless otherwise stated. D) Mechanical Control of Relaxation (relaxation rate versus strain rate relationship) increases with reduced preload. Data from preloads shown in Panels A (purple) and B (green) are shown in solid circles; data at further reduced preload (0.92 Lo of the trabeculae length, 0.95 Lo of the muscle length) shown as open circles. See Supplementary Fig. 1 for an example of how Panel C was derived; linearity of MCR (slope) is shown in Supplementary Fig. 4.

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  Fig. 2.. Relative MCR ratio for each trabecula. MCR was calculated for each muscle at Lo and again at reduced preload (0.95 Lo of the muscle length). Light colored shading indicates trabeculae with possible compliant attachments. On average, MCR increased by 20% (p < 0.001, one sample t-test, n = 14).

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  Fig. 3.. Model predicted forces of the 2-state myosin model based on fits to experimental data for the muscle at Lo (A, red lines) and reduced preload (B, blue lines). Length was calculated relative to trabecula length at Lo. Experimental data (Fig. 1) shown as thin lines (purple and green, respectively). The computed MCR data (C) for this model shows slopes greater than the experiment and do not replicate the preload dependent increase in MCR.

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  Fig. 4.. Peak fixed-end isometric tension and MCR after manual scaling of thin filament parameters. Parameter variation based on the 3-state mode with no force-dependent transitions. Only reduced cooperativity increases MCR faster than peak tension.

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  Fig. 5.. Peak fixed-end isometric tension and Mechanical Control of Relaxation after manual scaling of myosin transition rate parameters. Parameter variation based on the 3-state mode with no force-dependent transitions.

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  Fig. 6.. Model predicted forces of a 3-state model with force dependent detachment rates based on fits to experimental data for the muscle at Lo (A, redlines) and reduced preload (B, blue lines). Experimental data (Fig. 1) shown as thin lines (purple and green, respectively). Model fits continue to result in delayed and/or slowed isometric relaxation and a non-physiologic, accelerated relaxation after stretch. However, the computed MCR data (C) for this model begin to replicate the preload dependence observed in the experimental data.