title: Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model.
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.
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Darren T
authors.initials: DT
authors.lastname: Hwee
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Ryans
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Russell
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Hinken
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Cytokinetics, Inc., South San Francisco, California, United States of America.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jasper
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects* / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage*; D014336:Troponin / Q000235:genetics / Q000378:metabolism
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D011719:Pyrazines; D014336:Troponin