Molecular Basis of Mitochondrial Myopathy and Animal Models Related to the Energy Abnormality

线粒体肌病的分子基础和能量异常相关的动物模型

基本信息

批准号：
13670853
负责人：
KOGA Yasutoshi
金额：
$ 2.3万
依托单位：
KURUME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670853/
关键词：
Mitochondrial stroke endothelial dyfunction Nitric oxide Mitochondrial disease mitochondrial tRNA mutation L-arginine RNA19 Klotho Knockout mouse

项目摘要

Mitochondrial myopathy is a mutisystem disorders characterized by dysfunctions of mitochondrial energy metabolism. To investigate and clarify the molecular basis of mitochondrial myopathy, the creation of animal models is essential. In 1997, Klotho gene knockout mice have been developed as a model of human aging. However, there are no reports to investigate the molecular mechanism of abnormality in the mitochondrial energy metabolism in Klotho gene knockout mice. In this project, we planned to investigate the mitochondrial energy metabolism in Klotho gene knockout mice including mitochondrial respiratory chain enzyme, cytochrome contents, oxograph, uptake of neurotransmitters in synaptosome, muscle histochemistry and mitochondrial DNA abnormalities to evaluate the relationship between aging and mitochondrial energy metabolism.MELAS, is a maternally-inherited mitochondrial multisystem disorder, characterized early onset stroke before age 20. Mitochondrial angiopathy demonstrating degene … More rative change with increased abnormal mitochondria in the endothelial cells of intramuscular small arteries and arterioles has been reported in many MELAS patients. However, the primary cause for stroke-like episodes in young MELAS patients - whether mitochondrial cytopathy, angiopathy, or both - remains controversial. Based on a hypothesis that stroke-like episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered L-arginine to MELAS in the acute phase of stroke. We reported that L-arginine therapy quickly improved the symptoms of stroke in MELAS, improved the microcirculation, and also reduced tissue injury from ischemia. We demonstrated the pharmacological effects of L-arginine on the acute phase of stroke-like episodes to determine whether the plasma concentrations of biological parameters including L-arginine, NOx, or ADMA, the important regulatory factors to the endothelial functions, are changed in patients with MELAS compared with normal subjects. L-arginine therapy improved the microcirculation to reduce tissue injury from ischemia, and therefore constitutes a new potential therapy for use in the acute phase of strokelike episodes in MELAS. Less

线粒体肌病是一种以线粒体能量代谢功能障碍为特征的多系统疾病。为了研究和阐明线粒体肌病的分子基础，建立动物模型至关重要。1997年，Klotho基因敲除小鼠被开发为人类衰老模型。然而目前尚未有研究Klotho基因敲除小鼠线粒体能量代谢异常的分子机制的报道。本项目拟对Klotho基因敲除小鼠线粒体能量代谢进行研究。对小鼠进行线粒体呼吸链酶、细胞色素含量、氧谱、突触体中神经递质的摄取、肌肉组织化学和线粒体 DNA 异常等检查，以评估衰老与线粒体能量代谢之间的关系。MELAS，是一种母系遗传的线粒体多系统疾病，其特征为早发型中风20 岁之前。线粒体血管病表现出退化……更多相对变化，肌内小动脉内皮细胞中异常线粒体增加，据报道，许多 MELAS 患者中风样发作的主要原因（无论是线粒体细胞病、血管病还是两者兼而有之）仍存在争议。由于脑动脉血管舒张的节段性受损，我们在中风急性期给 MELAS 施用 L-精氨酸我们报道，L-精氨酸治疗迅速改善了 MELAS 的中风症状，改善了中风症状。我们证明了 L-精氨酸对中风样发作急性期的药理作用，以确定 L-精氨酸、NOx 或 ADMA 等生物参数的血浆浓度是否是重要的。与正常受试者相比，MELAS 患者的内皮功能调节因素发生了变化，L-精氨酸治疗改善了微循环，减少了缺血引起的组织损伤，因此构成了一种用于急性期的新的潜在疗法。 MELAS 中的中风样发作较少。