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

线粒体肌病是以线粒体能量代谢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，动物模型的建立是必不可少的。1997年，Klotho基因敲除小鼠被发展为人类衰老的模型。然而，关于Klotho基因敲除小鼠线粒体能量代谢异常的分子机制尚未见报道。本课题拟对Klotho基因敲除小鼠的线粒体能量代谢进行研究，包括线粒体呼吸链酶、细胞色素含量、氧分压、突触体对神经递质的摄取、肌肉组织化学和线粒体dna异常，以评价衰老与线粒体能量代谢的关系。MELAS是一种母系遗传性线粒体多系统疾病，以20岁前早发性卒中为特征。线粒体血管病表现为缺失基因…据报道，在许多MELAS患者中，肌肉内小动脉和小动脉内皮细胞的异常线粒体增加，这是更合理的变化。然而，年轻MELAS患者中风样发作的主要原因--无论是线粒体细胞病变、血管病变，还是两者兼而有之--仍然存在争议。基于MELAS卒中样发作是由脑动脉血管扩张节段性损害引起的假说，我们在卒中急性期给予MELAS应用L-精氨酸。我们报道，L-精氨酸治疗能迅速改善MELAS患者的中风症状，改善微循环，并减轻缺血所致的组织损伤。我们验证了L-精氨酸对卒中样发作急性期的药理作用，以确定MELAS患者血浆中内皮功能的重要调节因子L-精氨酸、NOx和ADMA的浓度是否与正常对照组相比发生了变化。L-精氨酸疗法可改善微循环，减少缺血对组织的损伤，从而构成一种新的潜在疗法，可用于MELAS卒中样发作的急性期。较少

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