Mechanisms of Mitochondrial Myopathy

描述（由申请人提供）：线粒体肌病是与线粒体呼吸链功能障碍相关的不同严重程度的疾病。线粒体功能障碍导致肌肉功能受损的机制尚不清楚，缺乏有效的治疗方法。初步数据表明，细胞内钙（Ca2+）处理的变化在收缩功能障碍中起关键作用，并提出了一种治疗这些疾病的新方法。这个转化项目的总体目标是确定线粒体肌病对肌肉功能影响的机制。该项目有三个具体目标：1)检查线粒体肌病小鼠模型及其对照小鼠离体骨骼肌细胞中Ca2-i的处理和力。测量Ca2+处理蛋白在小鼠疾病模型及其对照以及线粒体肌病患者的肌肉活检中的表达。2)研究线粒体肌病模型中线粒体Ca2+的变化及其与线粒体通透性过渡孔（MPTP）开放的关系。3)确定肌肉功能和Ca2+处理的缺陷是否可以通过MPTP抑制线粒体Ca2+摄取来逆转。线粒体疾病在临床特征和遗传原因上表现出很大的可变性，除了肌肉功能障碍外，还与许多疾病有关，包括2型糖尿病和心力衰竭。综上所述，它们被认为是最常见的先天性代谢错误，因此阐明缺陷的机制和治疗是重要的。拟议研究的结果将提供这方面的资料。

DESCRIPTION (provided by applicant): Mitochondrial myopathies are diseases of varying severity related to dysfunction of the mitochondrial respiratory chain. The mechanisms by which mitochondrial dysfunction cause impaired muscle function are poorly understood, and effective treatment is lacking. Preliminary data indicate that changes in intracellular calcium (Ca2+) handling play a key role in the contractile dysfunction, and a novel way to treat these diseases has been postulated. The overall goal of this translational project is to determine the mechanisms by which mitochondrial myopathy exerts its effects on muscle function. The project has three specific aims: 1) Examine global Ca2-i- handling and force in isolated skeletal muscle cells of mouse models of mitochondrial myopathy and their controls. Measure the expression of Ca2+ handling proteins in the mouse disease models and their controls as well as in muscle biopsies from patients with mitochondrial myopathies. 2) Examine the changes in mitochondrial Ca2+ in models of mitochondrial myopathy and their relation to opening of the mitochondrial permeability transition pore (MPTP). 3) Determine whether the defects in muscle function and Ca2+ handling can be reversed by inhibitors of mitochondrial Ca2+ uptake via the MPTP. Mitochondrial disorders show great variability in clinical features and genetic causes and in addition to muscle dysfunction have been implicated in numerous diseases, including type 2-diabetes and heart failure. Taken together they are regarded as the most common group of inborn errors of metabolism and it is therefore important to elucidate mechanisms of defects and treatments. Results of the proposed study will contribute such information.