Disclosure: R.H., K.G.S., W.C., A.J.R., M.M.C., V.V., D.J.M., A.A.W., and F.I.M. were employees and stockholders of Cytokinetics, Inc. (the study sponsor), at the time of the study. R.R.S. is an employee of Covance (Evansville, IN), where the study was conducted. S.B. and R.M.E. have received consulting fees from Cytokinetics, Inc. The design of the study protocols was the responsibility of the authors and Cytokinetics, Inc. (the sole funder of the study). All statistical analyses were done by Cytokinetics, Inc. All authors reviewed the manuscript and related documents in full, and approved submission. The corresponding author had full access to the study data and was responsible for submission of the manuscript.
Tirasemtiv amplifies skeletal muscle response to nerve activation in humans
Article first published online: 21 NOV 2014
© 2014 The Authors. Muscle Nerve published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Muscle & Nerve
Volume 50, Issue 6, pages 925–931, December 2014
How to Cite
Hansen, R., Saikali, K. G., Chou, W., Russell, A. J., Chen, M. M., Vijayakumar, V., Stoltz, R. R., Baudry, S., Enoka, R. M., Morgans, D. J., Wolff, A. A. and Malik, F. I. (2014), Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve, 50: 925–931. doi: 10.1002/mus.24239
This study was supported by Cytokinetics, Inc., South San Francisco, California.
- Issue published online: 21 NOV 2014
- Article first published online: 21 NOV 2014
- Accepted manuscript online: 13 MAR 2014 11:25PM EST
- Manuscript Accepted: 11 MAR 2014
- Cytokinetics, Inc., South San Francisco, California
- fast skeletal muscle troponin activator;
- force–frequency relationship;
- Phase 1;
- skeletal muscle;
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. Muscle Nerve 50: 925–931, 2014