Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations
Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations
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DOI：
10.1093/hmg/ddw388
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发表时间：
2017-01-15
影响因子：
3.5
通讯作者：
Treves, Susan
中科院分区：
文献类型：
--
作者：
Bachmann, Christoph;Jungbluth, Heinz;Treves, Susan
中心性肌病是由MTM1、DNM2、BIN1、RYR1和TTN等基因突变引起的早发性肌肉疾病。最严重和通常是致命的X连锁形式的肌管性肌病(XLMTM)是由编码普遍存在的脂肪磷酸酶肌管蛋白的基因突变引起的，肌管蛋白是一种专门去磷酸化磷脂酰肌醇-3-磷酸和磷脂酰肌醇-3，5-二磷酸的酶。由于XLMTM患者具有主要的肌肉特异性表型，许多致病机制已被提出，包括脂质积累对骨骼肌钙通道ryanodine受体1的直接影响，对细胞内细胞器结构的负面影响以及自噬缺陷。MTM1基因敲除的动物模型显示兰尼定受体1介导的钙释放严重减少，但由于敲除动物模型中的基因不一定复制人类的表型，我们认为直接研究MTM1突变对患者肌肉细胞的影响是很重要的。本研究的结果表明，在肌管水平上，MTM1突变并不显著影响通过兰尼定受体1介导的钙稳态和钙释放，尽管它们确实影响肌管的大小和核含量。另一方面，成熟肌肉，如那些从患者肌肉活检中获得的肌肉，显示出兰尼定受体1的表达显著减少，肌肉特异的microRNAs减少，组蛋白脱乙酰酶-4的表达显著上调。我们假设，主要基因突变导致的后一种情况是这些患者肌肉力量严重下降的原因。
Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients.