Tirasemtiv Amplifies Skeletal Muscle Response to Nerve Activation in Humans (P4.077) (2014)

OBJECTIVE: This study 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 healthy human volunteers.
 BACKGROUND: Tirasemtiv sensitizes fast skeletal muscle to calcium. In preclinical models of nerve-muscle function, muscle force increased within the operating range of motor unit discharge rates associated with the voluntary activation of skeletal muscle. More recently, potentially clinically relevant pharmacodynamic effects of tirasemtiv have been observed in patients with amyotrophic lateral sclerosis, with myasthenia gravis, and with calf claudication due to peripheral artery disease. Here we assessed the effect of tirasemtiv on skeletal muscle function in healthy volunteers by measuring the change in the isometric force-frequency response of the tibialis anterior muscle.
 DESIGN/METHODS: Healthy men received single doses of tirasemtiv at 250 mg, 500 mg, 1000 mg, and placebo in a randomized, double-blind, 4-period crossover design. The deep peroneal 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 before and at 3, 5, and 7 hours following each dose.
 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 sub-tetanic nerve stimulation frequencies (10 Hz).
 CONCLUSIONS: These data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans, especially at low to mid-range stimulation frequencies. This outcome provides support for further studies of tirasemtiv as a potential therapeutic approach in conditions marked by diminished neuromuscular input.
 Study Supported by: Cytokinetics, Inc. Disclosure: Dr. Malik has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Malik holds stock and/or stock options in Cytokinetics Inc. which sponsored research in which Dr. Malik was involved as an investigator. Dr. Malik has received research support from Cytokinetics Inc. Dr. Hansen has received personal compensation for activities with Cytokinetics, Inc. as an employee. Mr. Vijayakumar has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Randall has received personal compensation for activities with Covance, and Cytokinetics Inc. Dr. Enoka has received personal compensation for activities with Cytokinetics, Inc. as a member of the Scientific Advisory Board. Dr. Morgans has received personal compensation for activities with Cytokinetics, Inc. Dr. Wolff has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Wolff holds stock and/or stock options in Cytokinetics, Inc. which sponsored research in which Dr. Wolff was involved as an investigator. Dr. Wolff has received research support from Cytokinetics, Inc.