Elucidating the Contribution of Skeletal Muscle Ion Channels to Amyotrophic Lateral Sclerosis in search of new therapeutic options.

摘要: The discovery of pathogenetic mechanisms is essential to identify new therapeutic approaches in Amyotrophic Lateral Sclerosis (ALS). Here we investigated the role most important ion channels skeletal muscle an ALS animal model (MLC/SOD1G93A) carrying a mutated SOD1 exclusively this tissue, avoiding motor-neuron involvement. Ion are fundamental proteins for function, and also sustain neuromuscular junction nerve integrity. By multivariate statistical analysis, using machine learning algorithms, identified discriminant genes MLC/SOD1G93A mice. Surprisingly, expression ClC-1 chloride channel, present only muscle, was reduced. Also, Protein Kinase-C, known control activity, increased, causing its inhibition. functional characterization confirmed reduction leading hyperexcitability impaired relaxation. increased channel coupled AMPA-receptor may contribute sustained depolarization impairment. decreased irisin, muscle-secreted peptide protecting brain disturb muscle-nerve connection. Interestingly, in-vitro application chelerythrine or acetazolamide, restored activity sarcolemma these These findings show that function impairment lead vulnerability, opens possibility investigate on compounds as promising therapy.