Characterization of hereditary inclusion body myopathy myoblasts: Possible primary impairment of apoptotic events
Characterization of hereditary inclusion body myopathy myoblasts: Possible primary impairment of apoptotic events
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DOI：
10.1038/sj.cdd.4402208
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发表时间：
2007-11-01
影响因子：
12.4
通讯作者：
Mitrani-Rosenbaum, S.
中科院分区：
文献类型：
--
作者：
Amsili, S.;Shlomai, Z.;Mitrani-Rosenbaum, S.
遗传性包涵体肌病（HIBM）是一种独特的肌肉疾病引起的UDP-N-乙酰葡糖胺2-差向异构酶/N-乙酰甘露糖胺激酶（GNE）基因突变。GNE编码在唾液酸的生物合成途径中起作用的双功能酶。由于导致疾病表型的潜在的肌肉病理学机制知之甚少，我们建立了人成肌细胞培养物，来自携带纯合M712 T突变的HIBM卫星细胞，并鉴定了这些细胞的细胞和分子特征。HIBM和对照组成肌细胞表现出相似的异质性模式的增殖和分化。在细胞凋亡诱导，磷脂酰丝氨酸外化是相似的HIBM和控制。相比之下，与对照相比，在大多数HIBM培养物中，caspase-3和-9的活性形式强烈增强，而在对照中下调的pAkt在HIBM细胞中保持高水平。这些结果可能表明HIBM细胞中的凋亡信号传导受损。由于卫星细胞能够使有丝分裂后的肌肉组织部分再生，这些改变的过程可能导致患者中观察到的肌肉质量损失。HIBM影响的肌细胞中的存活缺陷的鉴定可以揭示GNE在肌细胞中的新功能。
Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells.