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.
摘要:
肌营养不良是遗传性神经肌肉疾病,导致进行性残疾,并经常影响预期寿命。最严重的,常见类型是Duchenne型肌营养不良症(DMD)和肢带肌球蛋白病,导致肌肉无力和消瘦。这些疾病有共同的病理机制,由于锚定肌营养不良蛋白(DMD,肌营养不良蛋白病)或由于肌聚糖编码基因(LGMDR3至LGMDR6)的突变,α-肌糖胞外ATP酶活性丧失。这扰乱了重要的嘌呤能信号:急性肌肉损伤导致大量ATP的释放,它充当与损伤相关的分子模式(DAMP)。DAMPs引发炎症,清除死亡组织并启动再生,最终恢复正常的肌肉功能。然而,在DMD和LGMD中,胞外ATP酶活性的丧失,通常会减少这种细胞外ATP(eATP)诱发的刺激,导致极高的eATP水平。因此,在营养不良的肌肉中,急性炎症变得慢性和破坏性。非常高的eATP过度激活P2X7嘌呤受体,不仅维持炎症,而且还将营养不良肌细胞中潜在的补偿性P2X7上调调整为细胞损伤机制,从而加剧病理。因此,P2X7受体在营养不良的肌肉是一个特定的治疗靶点。因此,P2X7阻断剂可减轻肌营养不良蛋白病和肌糖病小鼠模型的营养不良性损伤。因此,现有的P2X7受体阻滞剂应该被考虑用于治疗这些高度衰弱的疾病.这篇综述旨在介绍eATP-P2X7嘌呤受体轴在肌营养不良的发病机制和治疗中的最新认识。