title: Tirasemtiv amplifies skeletal muscle response to nerve activation in humans.
abstract: BACKGROUND
  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.
authors.affiliation: Research and Early Development, Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080-4808, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Hansen
authors.forename: Khalil G
authors.initials: KG
authors.lastname: Saikali
authors.forename: Willis
authors.initials: W
authors.lastname: Chou
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Russell
authors.forename: Michael M
authors.initials: MM
authors.lastname: Chen
authors.forename: Vipin
authors.initials: V
authors.lastname: Vijayakumar
authors.forename: Randall R
authors.initials: RR
authors.lastname: Stoltz
authors.forename: Stephane
authors.initials: S
authors.lastname: Baudry
authors.forename: Roger M
authors.initials: RM
authors.lastname: Enoka
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004558:Electric Stimulation; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology; D009465:Neuromuscular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D020107:Troponin T / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D009465:Neuromuscular Agents; D011719:Pyrazines; C518660:TNNT3 protein, human; D020107:Troponin T
keywords: Phase 1; fast skeletal muscle troponin activator; force-frequency relationship; skeletal muscle; tirasemtiv