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

Scientific Reports
Giulia Maria CamerinoSabata Pierno

Abstract

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

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Citations

Oct 4, 2019·The Journal of Pathology·Jenna M GregoryColin Smith
Jul 4, 2020·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·John P FranklinMichael G Hanna
Aug 2, 2020·British Journal of Pharmacology·Valle PalomoAna Martinez
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May 4, 2020·Pflügers Archiv : European journal of physiology·Concetta AltamuraPaola Imbrici
Nov 11, 2020·International Journal of Molecular Sciences·Mercedes Lachén-MontesEnrique Santamaría
Mar 7, 2021·International Journal of Molecular Sciences·Giulia Maria CamerinoSabata Pierno
Apr 5, 2021·Materials Science & Engineering. C, Materials for Biological Applications·Jesús CirizaPatricia Rico
Aug 7, 2021·Journal of Personalized Medicine·Oihane Pikatza-MenoioSonia Alonso-Martín
Jan 20, 2021·CNS & Neurological Disorders Drug Targets·Fatima MaqoudDomenico Tricarico

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Methods Mentioned

BETA
transgenic
PCR
PCA
dissection

Software Mentioned

Scipy
ACTZ
Image Lab
Seaborn
GraphPad
- LDA ( Principal Component Analysis and Linear Discriminant A...
CLAMPFIT
Scikit
Normfinder
svd

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