Tirasemtiv amplifies skeletal muscle response to nerve activation in humans

Abstract

Introduction: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans.

Methods: Healthy men received tirasemtiv and placebo in a randomized, double-blind, 4-period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force-frequency relationship of tibialis anterior dorsiflexion was assessed after dosing.

Results: Tirasemtiv increased force produced by the tibialis anterior in a dose-, concentration-, and frequency-dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz).

Conclusions: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input.

Keywords: Phase 1; fast skeletal muscle troponin activator; force-frequency relationship; skeletal muscle; tirasemtiv.

FIGURE 1

Example force profiles and force–frequency response. (A) One set (of 3) normalized force profiles from a stimulation protocol. The forces (lowest to highest) were elicited with 800-ms stimulus trains of 5, 7.5, 10, 12.5, 15, 17.5, 25, and 50 Hz. The forces were normalized to the peak force elicited with 50-Hz stimulation. (B) An example of the normalized force–frequency response at a single time-point (5 hours). Peak forces (mean ± SEM) from each of the 3 replicates at each stimulation frequency were normalized to the 50-Hz average peak force.

FIGURE 2

Tirasemtiv increases the response of muscle to neuromuscular activation in a dose- and concentration-related manner. (A) The placebo-subtracted summed mean percent change from baseline of peak force (%ΣF) is plotted in (A) (± SEM) from each assessment time-point for 250-, 500-, and 1000-mg doses. Asterisks denote statistical significance (P < 0.05) compared with placebo. The lines with circles, squares, and triangles are the average plasma concentrations for each population for the 250-, 500-, and 1000-mg doses, respectively. (B) The placebo-subtracted percent change in peak force (%F) is plotted. Mean ± SEM data for each tirasemtiv plasma level concentration bin are plotted for each stimulus frequency. Asterisks denote statistical significance (P < 0.05).