Mitochondrial Dysfunction in Skeletal Muscle of Amyloid Precursor Protein-overexpressing Mice
Mitochondrial Dysfunction in Skeletal Muscle of Amyloid Precursor Protein-overexpressing Mice
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DOI：
10.1074/jbc.m112.359588
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发表时间：
2012-06-08
影响因子：
4.8
通讯作者：
Shtifman, Alexander
中科院分区：
文献类型：
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作者：
Boncompagni, Simona;Moussa, Charbel E. -H.;Shtifman, Alexander
包涵体肌炎是老年人最常见的肌肉疾病，其部分特征在于淀粉样前体蛋白（APP）的异常表达及其蛋白水解片段（统称为β-淀粉样蛋白）的细胞内积累。本研究检测了β-淀粉样蛋白积累对转基因小鼠（MCK-beta APP）骨骼肌线粒体结构和功能的影响，转基因小鼠被设计为积累肌纤维内β-淀粉样蛋白。电子显微镜分析显示，2-3个月大的MCK-β APP小鼠的大部分肌纤维在线粒体和其他细胞器中含有许多异质性改变。[H-1-去偶联] C-13 NMR光谱显示TCA循环活性显著降低，并表明MCK-β APP肌肉中葡萄糖代谢从有氧转换为无氧。从MCK-β APP小鼠分离的肌纤维也表现出细胞质pH值降低、ROS产生速率增加和质膜部分去极化。用线粒体钙单向转运体拮抗剂Ru 360处理MCK-β APP肌细胞，逆转了质膜电位（V-m）和pH值的改变。与细胞氧化还原状态的改变一致，用谷胱甘肽处理MCK-β APP肌细胞逆转了β-淀粉样蛋白积累对Ca 2+瞬时振幅的影响。我们的结论是，线粒体的结构和功能的改变之前，在MCK-β APP小鼠的组织病理学和临床特征的报告出现，并可能代表包涵体肌炎的发病机制中的关键早期事件。
Inclusion body myositis, the most common muscle disorder in the elderly, is partly characterized by abnormal expression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragments collectively known as beta-amyloid. The present study examined the effects of beta-amyloid accumulation on mitochondrial structure and function of skeletal muscle from transgenic mice (MCK-beta APP) engineered to accumulate intramyofiber beta-amyloid. Electron microscopic analysis revealed that a large fraction of myofibers from 2-3-month-old MCK-beta APP mice contained numerous, heterogeneous alterations in mitochondria, and other cellular organelles. [H-1-decoupled] C-13 NMR spectroscopy showed a substantial reduction in TCA cycle activity and indicated a switch from aerobic to anaerobic glucose metabolism in the MCK-beta APP muscle. Isolated muscle fibers from the MCK-beta APP mice also exhibited a reduction in cytoplasmic pH, an increased rate of ROS production, and a partially depolarized plasmalemma. Treatment of MCK-beta APP muscle cells with Ru360, a mitochondrial Ca2+ uniporter antagonist, reversed alterations in the plasmalemmal membrane potential (V-m) and pH. Consistent with altered redox state of the cells, treatment of MCK-beta APP muscle cells with glutathione reversed the effects of beta-amyloid accumulation on Ca2+ transient amplitudes. We conclude that structural and functional alterations in mitochondria precede the reported appearance of histopathological and clinical features in the MCK-beta APP mice and may represent key early events in the pathogenesis of inclusion body myositis.