Contingent intramuscular boosting of P2XR7 axis improves motor function in transgenic ALS mice

Paola Fabbrizio,Eliana Sammali,Giulia Mella,Valentina Bonetto,Flavia Raggi,Jessica D’Agostino,Gianni Sorarù,Caterina Bendotti,Laura Pasetto,Nicolò Panini,Giovanni Nardo,Cassandra Margotta

doi:10.1007/s00018-021-04070-8

Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons and severe muscle atrophy without effective treatment. Most research on the disease has been focused on studying motor neurons and supporting cells of the central nervous system. Strikingly, the recent observations have suggested that morpho-functional alterations in skeletal muscle precede motor neuron degeneration, bolstering the interest in studying muscle tissue as a potential target for the delivery of therapies. We previously showed that the systemic administration of the P2XR7 agonist, 2′(3′)-O‐(4-benzoylbenzoyl) adenosine 5-triphosphate (BzATP), enhanced the metabolism and promoted the myogenesis of new fibres in the skeletal muscles of SOD1G93A mice. Here we further corroborated this evidence showing that intramuscular administration of BzATP improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of infiltrating macrophages. The preservation of the skeletal muscle retrogradely propagated along with the motor unit, suggesting that backward signalling from the muscle could impinge on motor neuron death. In addition to providing the basis for a suitable adjunct multisystem therapeutic approach in ALS, these data point out that the muscle should be at the centre of ALS research as a target tissue to address novel therapies in combination with those oriented to the CNS.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterised by degenerative changes in upper and lower motor neurons [1, 2]
The independent experiments for each experimental group are scattered on the graph at each time point.*P < 0.05, **P < 0.01, ****P < 0.0001 by one-way ANOVA with Tukey’s post-analysis
We showed that the intramuscular boosting of the P2X receptor 7 (P2XR7) signalling in the skeletal muscles of SOD1G93A mice improved the motor performance by decreasing the

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterised by degenerative changes in upper and lower motor neurons [1, 2]. Symptoms typically occur in late middle life and present as relentlessly progressive muscle atrophy and weakness, with the effects on respiratory muscles limiting survival to 2–4 years after disease onset in most cases [1, 3]. The current treatment options are based on the symptom management and respiratory support with the only approved medications. While most ALS cases are sporadic (sALS), about 10% are familial (fALS) and characterised by autosomal dominant inheritance [5]. The genetic causes of fALS, with approximately 40–55% of cases, accounted for variants in known ALS-linked genes [6]. More than 50 potentially causative or disease-modifying genes have been identified, pathogenic modifications in SOD1, TARDBP, FUS and C9ORF72 occur most frequently, with diseasecausing variants in other genes being relatively uncommon [5]. The diagnostic advancements have only helped explain a fraction of sALS cases, with the aetiology remaining unexplained in over 90% of patients [7]

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