The Role of P2X7 Purinoceptors in the Pathogenesis and Treatment of Muscular Dystrophies

Author:

Zabłocki Krzysztof1,Górecki Dariusz C.2ORCID

Affiliation:

1. Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland

2. School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK

Abstract

Muscular dystrophies are inherited neuromuscular diseases, resulting in progressive disability and often affecting life expectancy. The most severe, common types are Duchenne muscular dystrophy (DMD) and Limb-girdle sarcoglycanopathy, which cause advancing muscle weakness and wasting. These diseases share a common pathomechanism where, due to the loss of the anchoring dystrophin (DMD, dystrophinopathy) or due to mutations in sarcoglycan-encoding genes (LGMDR3 to LGMDR6), the α-sarcoglycan ecto-ATPase activity is lost. This disturbs important purinergic signaling: An acute muscle injury causes the release of large quantities of ATP, which acts as a damage-associated molecular pattern (DAMP). DAMPs trigger inflammation that clears dead tissues and initiates regeneration that eventually restores normal muscle function. However, in DMD and LGMD, the loss of ecto-ATPase activity, that normally curtails this extracellular ATP (eATP)-evoked stimulation, causes exceedingly high eATP levels. Thus, in dystrophic muscles, the acute inflammation becomes chronic and damaging. The very high eATP over-activates P2X7 purinoceptors, not only maintaining the inflammation but also tuning the potentially compensatory P2X7 up-regulation in dystrophic muscle cells into a cell-damaging mechanism exacerbating the pathology. Thus, the P2X7 receptor in dystrophic muscles is a specific therapeutic target. Accordingly, the P2X7 blockade alleviated dystrophic damage in mouse models of dystrophinopathy and sarcoglycanopathy. Therefore, the existing P2X7 blockers should be considered for the treatment of these highly debilitating diseases. This review aims to present the current understanding of the eATP-P2X7 purinoceptor axis in the pathogenesis and treatment of muscular dystrophies.

Funder

Defence and Security Accelerator

Royal Society International Exchanges grant

COST

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. ATP as a signaling molecule;The Ukrainian Biochemical Journal;2024-06-14

2. Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy;Current Issues in Molecular Biology;2024-01-29

3. Energy Regulation in Inflammatory Sarcopenia by the Purinergic System;International Journal of Molecular Sciences;2023-11-29

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