Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model
Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model
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DOI：
10.1038/nm.1956
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发表时间：
2009-06-01
期刊：
影响因子：
82.9
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
--
作者：
Malicdan, May Christine V.;Noguchi, Satoru;Nishino, Ichizo
伴边缘空泡远端肌病 (DMRV)-遗传性包涵体肌病 (hIBM) 是一种成人发病、中度进行性常染色体隐性遗传肌病；最终，受影响的人只能坐轮椅(1)。其临床特征为骨骼肌萎缩和无力，病理特征为镶边空泡，这些空泡实际上是自噬空泡的堆积(2-4)、散在的角纤维以及淀粉样蛋白和其他蛋白质的细胞内堆积(5)。迄今为止，还没有针对这种衰弱性肌病的治疗方法，主要是因为该疾病的病理机制一直是个谜。已知DMRV-hIBM的致病基因是GNE，编码葡萄糖胺(UDP-N-乙酰基)-2-差向异构酶和N-乙酰甘露糖胺激酶(6-8)——唾液酸生物合成中的两种必需酶(9)。然而，目前尚不清楚唾液酸产生减少是否会导致肌肉退化，因为 GNE 已被认为具有唾液酸生物合成以外的作用 (10-12)。通过证明在口服唾液酸代谢物治疗后，DMRV-hIBM 小鼠模型中的肌肉萎缩和无力得到了完全预防，我们提供了证据表明低唾液酸化确实是 DMRV-hIBM 病理机制的关键因素之一。这些结果支持了这样的观点，即 DMRV-hIBM 可以通过简单地给予唾液酸来治疗，这种策略可以在不久的将来应用于临床试验。
Distal myopathy with rimmed vacuoles (DMRV)-hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound(1). It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles(2-4), scattered angular fibers and intracellular accumulation of amyloid and other proteins(5). To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase(6-8)-two essential enzymes in sialic acid biosynthesis(9). It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid biosynthesis(10-12). By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future.