P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis.

Muscle weakness plays an important role in neuromuscular disorders comprisingamyotrophic lateral sclerosis (ALS). However, it is not established whether muscledenervation originates from the motor neurons, the muscles or more likely both.Previous studies have shown that the expression of the SOD1G93A mutation inskeletal muscles causes denervation of the neuromuscular junctions, inability toregenerate and consequent atrophy, all clear symptoms of ALS. In this work, weused SOD1G93A mice, a model that best mimics some pathological features ofboth familial and sporadic ALS, and we investigated some biological effects inducedby the activation of the P2X7 receptor in the skeletal muscles. The P2X7, belongingto the ionotropic family of purinergic receptors for extracellular ATP, is abundantlyexpressed in the healthy skeletal muscles, where it controls cell duplication, differentiation,regeneration or death. In particular, we evaluated whether an in vivotreatment in SOD1G93A mice with the P2X7 specific agonist 2?(3?)-O-(4-Benzoylbenzoyl)adenosine5?-triphosphate (BzATP) just before the onset of a pathologicalneuromuscular phenotype could exert beneficial effects in the skeletal muscles. Ourfindings indicate that stimulation of P2X7 improves the innervation and metabolismof myofibers, moreover elicits the proliferation/differentiation of satellite cells, thuspreventing the denervation atrophy of skeletal muscles in SOD1G93A mice. Overall,this study suggests that a P2X7-targeted and site-specific modulation might be astrategy to interfere with the complex multifactorial and multisystem nature of ALS.