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Τρίτη 12 Ιουνίου 2018

A spatially explicit model shows how titin stiffness modulates muscle mechanics and energetics

Abstract
In striated muscle, the giant protein titin spans the entire length of a half-sarcomere and extends from the backbone of the thick filament, reversibly attaches to the thin filaments, and anchors to the dense protein network of the z-disk capping the end of the half-sarcomere. However, little is known about the relationship between the basic mechanical properties of titin and muscle contractility. Here, we build upon our previous multi-filament, spatially explicit computational model of the half-sarcomere by incorporating the nonlinear mechanics of titin filaments in the I-band. We vary parameters of the nonlinearity to understand the effects of titin stiffness on contraction dynamics and efficiency. We do so by simulating isometric contraction for a range of sarcomere lengths (SL; 1.6–3.25 μm). Intermediate values of titin stiffness accurately reproduce the passive force–SL relation for skeletal muscle. The maximum force–SL relation is not affected by titin for SL ≤ 2.5 μm. However, as titin stiffness increases, maximum force for the four thick filament system at SL = 3.0 μm significantly decreases from 103.2 ± 2 pN to 58.8 ± 1 pN. Additionally, by monitoring ATP consumption, we measure contraction efficiency as a function of titin stiffness. We find that at SL = 3.0 μm, efficiency significantly decreases from 13.9 ± 0.4 pN/ATP to 7.0 ± 0.3 pN/ATP when increasing titin stiffness, with little or no effect below 2.5 μm. Taken together, our results suggest that, despite an increase in the fraction of motors bound to actin along the descending limb when titin is stiffer, the force-generating capacity of the motors is reduced. These results suggest that titin stiffness has the potential to affect contractile efficiency.

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