Identifying Potential Therapeutic Approaches in Neurodegenerative Diseases

Spinal and Bulbar Muscular Atrophy (SBMA) and Amyotrophic Lateral Sclerosis (ALS) are motor neuron diseases (MND) characterized by motor neuron death leading to movement disorders, progressive muscle atrophy, fasciculations, muscle weakness and in some cases causes the death of the patients. Skeletal muscle remains one of the primary organs for the disease progression and excitotoxicity has been implicated in MND’s which is a result of elevated ionic conductance irregularity. However, the mechanism relating to ion channel dysregulation in the skeletal muscle remains unexplored. We investigated the physiological transcript levels of ion channels across mice lifespan and different skeletal muscles, where we observed a gradual trend of increase with age and skeletal muscle specific expression. With the immunofluorescence we identified Type 2a and 2x fiber type specific expression of target ion channel. Additionally, a close proximity with Dihydropyridine Receptor (DHPR) was revealed with co-staining experiments and its localization on the Transverse tubules (T-tubules). Furthermore, ex-vivo muscle force experiment on Extensor Digitorum Longus (EDL) of mice treated with ion channel modulators suggested an increase in contraction time suggesting a potential role of target ion channels in the skeletal muscle excitation-contraction. To elucidate the regulation of channel’s transcript levels, motor unit impairment was induced via various methods: nerve resection (physical denervation), BaCl2 injections (muscle damage), and botulinum toxin injections (functional denervation). Collectively, these results propose that motor unit impairment contributes to the downregulation of target ion channels. This downregulation has also been observed in SBMA and ALS mice models. Additionally, treatment with channel modulator to SBMA transgenic mice showed no significant difference in the behavioural measurements and warrants an alternative strategy to target ion channels such as targeting miRNA specific for ion channel transcript or overexpression system in skeletal muscle of transgenic mice models. The vulnerability of ion channels to motor unit damage, as evident in disease models, underscores their potential significance in skeletal muscle function and warrants further investigation.