PLoS ONE (Jan 2014)

Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model.

  • Darren T Hwee,
  • Adam Kennedy,
  • Julie Ryans,
  • Alan J Russell,
  • Zhiheng Jia,
  • Aaron C Hinken,
  • David J Morgans,
  • Fady I Malik,
  • Jeffrey R Jasper

DOI
https://doi.org/10.1371/journal.pone.0096921
Journal volume & issue
Vol. 9, no. 5
p. e96921

Abstract

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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1 G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1 G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.