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-SOD1G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a debilitating and fatal disease characterized by the selective and progressive loss of motor neurons in the spinal cord leading to atrophy, weakness, and eventually complete paralysis of skeletal muscle
Many of the histological features of disease in the B6SJL-SOD1G93A mice are similar to those observed in ALS patients, there appears to be less robust enlargement and sprouting of neighboring motor units towards denervated muscles as compensation for the loss of the primary motor neuron [4]
Our results demonstrate that tirasemtiv improves muscle strength in B6SJLSOD1G93A mice exhibiting functional deficits, and supports the hypothesis that tirasemtiv may benefit patients with ALS or other neuromuscular diseases that exhibit impaired neural input
Summary
Amyotrophic Lateral Sclerosis (ALS) is a debilitating and fatal disease characterized by the selective and progressive loss of motor neurons in the spinal cord leading to atrophy, weakness, and eventually complete paralysis of skeletal muscle. Many of the histological features of disease in the B6SJL-SOD1G93A mice are similar to those observed in ALS patients, there appears to be less robust enlargement and sprouting of neighboring motor units towards denervated muscles as compensation for the loss of the primary motor neuron [4]. The only approved medication for ALS patients to date is riluzole, which potentially extends life an average of 2 to 3 months, and extends lifespan in the B6SJL-SOD1G93A mouse [5,6]. Riluzole has not been shown to improve muscle strength or respiratory function in ALS patients [7]
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