Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

被引：52

作者：

Hwee, Darren T. ^{[1
]}

Kennedy, Adam ^{[1
]}

Ryans, Julie ^{[1
]}

Russell, Alan J. ^{[1
]}

Jia, Zhiheng ^{[1
]}

Hinken, Aaron C. ^{[1
]}

Morgans, David J. ^{[1
]}

Malik, Fady I. ^{[1
]}

Jasper, Jeffrey R. ^{[1
]}

机构：

[1] Cytokinet Inc, San Francisco, CA 94080 USA

来源：

PLOS ONE | 2014年 / 9卷 / 05期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DEGENERATION; TIME-COURSE; RILUZOLE; MUTATION; IGF-1; MICE;

D O I：

10.1371/journal.pone.0096921

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

共 25 条

[1] A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis [J].