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

PLoS One. 2014 May 7;9(5):e96921. doi: 10.1371/journal.pone.0096921. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal
  • Female
  • Humans
  • Imidazoles / administration & dosage*
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / pathology
  • Muscle Strength / drug effects*
  • Muscle Strength / genetics
  • Muscle, Skeletal / drug effects
  • Pyrazines / administration & dosage*
  • Troponin / genetics
  • Troponin / metabolism

Substances

  • CK-2017357
  • Imidazoles
  • Pyrazines
  • Troponin

Grant support

Cytokinetics, Inc. funded this study and provided support in the form of salaries for all authors, whose roles included study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.