Publication News: AKAY Lab
Unlocking new mechanisms for future ALS therapies: early interventions with cholinergic antagonists reduce neuromuscular decline
Reynaldo Popoli, Tyler L. Wells, and Turgay Akay
Published: 2025 Oct 15 Journal of Neurophysiology Volume 134, Issue 4
Link: https://doi.org/10.1152/jn.00306.2025
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterized by motor neuron loss, leading to muscle paralysis and death. C-boutons have been shown to be part of the compensatory mechanism behind delayed symptom onset, and are most active during vigorous exercises, like swimming. When mutant mice with silenced C-boutons perform this exercise, disease progression and behavioral performance drastically improve. Genetic manipulation of C-boutons in human patients remains limited, therefore, we sought to manipulate these synapses using cholinergic antagonists in the presence and absence of exercise in a mouse model of ALS. We demonstrate that atropine and methoctramine administration yield significant improvements in human endpoints, weight maintenance, treadmill performance, and grip strength. Most remarkably, muscle innervation was greatly enhanced at humane endpoints compared with controls, suggesting these drugs provide a protective effect against loss of motor control. We found that methoctramine provided greater benefits in the absence of exercise, hinting at the presence of novel cholinergic mechanisms that can be manipulated to preserve motor function. Moreover, we provide evidence that these results are independent of C-boutons, and that methoctramine does not appear to cross the blood-brain barrier (BBB). Our results reveal pharmacological mechanisms by which muscle denervation can be reduced, thereby decreasing the rate of disease progression. We have uncovered a promising avenue for improving ALS symptoms by pharmacologically manipulating cholinergic transmission. This mechanism presents as a possible therapy translatable to the clinical setting, which has the potential to prevent the loss of motor control in patients with ALS.NEW & NOTEWORTHY This study shows that blocking M2 receptors with methoctramine improves motor function and muscle innervation in an amyotrophic lateral sclerosis (ALS) mouse model, particularly in the absence of exercise. Further evaluation suggests that some of these beneficial effects are related to a peripheral mechanism. These findings highlight a potential new therapeutic approach for ALS that targets cholinergic signaling.