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Force Responses and Sarcomere Dynamics of Cardiac Myofibrils Induced by Rapid Changes in [Pi].

ABSTRACT: The second phase of the biphasic force decay upon release of phosphate from caged phosphate was previously interpreted as a signature of kinetics of the force-generating step in the cross-bridge cycle. To test this hypothesis without using caged compounds, force responses and individual sarcomere dynamics upon rapid increases or decreases in concentration of inorganic phosphate [Pi] were investigated in calcium-activated cardiac myofibrils. Rapid increases in [Pi] induced a biphasic force decay with an initial slow decline (phase 1) and a subsequent 3-5-fold faster major decay (phase 2). Phase 2 started with the distinct elongation of a single sarcomere, the so-called sarcomere "give". "Give" then propagated from sarcomere to sarcomere along the myofibril. Propagation speed and rate constant of phase 2 (k+Pi(2)) had a similar [Pi]-dependence, indicating that the kinetics of the major force decay (phase 2) upon rapid increase in [Pi] is determined by sarcomere dynamics. In contrast, no "give" was observed during phase 1 after rapid [Pi]-increase (rate constant k+Pi(1)) and during the single-exponential force rise (rate constant k-Pi) after rapid [Pi]-decrease. The values of k+Pi(1) and k-Pi were similar to the rate constant of mechanically induced force redevelopment (kTR) and Ca2+-induced force development (kACT) measured at same [Pi]. These results indicate that the major phase 2 of force decay upon a Pi-jump does not reflect kinetics of the force-generating step but results from sarcomere "give". The other phases of Pi-induced force kinetics that occur in the absence of "give" yield the same information as mechanically and Ca2+-induced force kinetics (k+Pi(1) ? k-Pi ? kTR ? kACT). Model simulations indicate that Pi-induced force kinetics neither enable the separation of Pi-release from the rate-limiting transition f into force states nor differentiate whether the "force-generating step" occurs before, along, or after the Pi-release.

SUBMITTER: Stehle R

PROVIDER: S-EPMC5266088 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Publications

Force Responses and Sarcomere Dynamics of Cardiac Myofibrils Induced by Rapid Changes in [Pi].

Stehle Robert R

Biophysical journal 20170101 2

The second phase of the biphasic force decay upon release of phosphate from caged phosphate was previously interpreted as a signature of kinetics of the force-generating step in the cross-bridge cycle. To test this hypothesis without using caged compounds, force responses and individual sarcomere dynamics upon rapid increases or decreases in concentration of inorganic phosphate [Pi] were investigated in calcium-activated cardiac myofibrils. Rapid increases in [Pi] induced a ...[more]

PMID: 28122221

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Project description:The sarcomere length non-uniformity theory (SLNT) is a widely accepted explanation for residual force enhancement (RFE). RFE is the increase in steady-state isometric force following active muscle stretching. The SLNT predicts that active stretching of a muscle causes sarcomere lengths (SL) to become non-uniform, with some sarcomeres stretched beyond actin-myosin filament overlap (popping), causing RFE. Despite being widely known, this theory has never been directly tested. We performed experiments on isolated rabbit muscle myofibrils (n?=?12) comparing SL non-uniformities for purely isometric reference contractions (I-state) and contractions following active stretch producing RFE (FE-state). Myofibrils were activated isometrically along the descending limb of the force-length relationship (mean?±?1 standard deviation (SD)?=?2.8?±?0.3?µm sarcomere(-1)). Once the I-state was reached, myofibrils were shortened to an SL on the plateau of the force-length relationship (2.4?µm sarcomere(-1)), and then were actively stretched to the reference length (2.9?±?0.3?µm sarcomere(-1)). We observed RFE in all myofibrils (39?±?15%), and saw varying amounts of non-uniformity (1 SD?=?0.9?±?0.5?µm) that was not significantly correlated with the amount of RFE, but through pairwise comparisons was found to be significantly greater than the non-uniformity measured for the I-state (0.7?±?0.4?µm). Three myofibrils exhibited no increase in non-uniformity. Active stretching was accompanied by sarcomere popping in four myofibrils, and seven had popped sarcomeres in the I-state. These results suggest that, while non-uniformities are present with RFE, they are also present in the I-state. Furthermore, non-uniformity is not associated with the magnitude of RFE, and myofibrils that had no increase in non-uniformity with stretch still showed normal RFE. Therefore, it appears that SL non-uniformity is a normal associate of muscle contraction, but does not contribute to RFE following active stretching of isolated skeletal muscle myofibrils.

Dataset Information

Force Responses and Sarcomere Dynamics of Cardiac Myofibrils Induced by Rapid Changes in [Pi].

Publications

Force Responses and Sarcomere Dynamics of Cardiac Myofibrils Induced by Rapid Changes in [P<sub>i</sub>].

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