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疾病。肌肉功能缺陷在线粒体疾病中很常见，目前缺乏有效的治疗方法。虽然关于基因突变作为线粒体肌病的原因的知识基础正在增加，但对线粒体功能障碍如何导致肌肉功能受损知之甚少。阐明这些致病机制将有助于开发药物治疗，从而提高这些疾病患者的生活质量。该项目的最终目标是改善线粒体肌病的治疗，从长远来看，也可以治疗受人类线粒体功能障碍影响的其他器官的缺陷。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。在专门设计的小鼠模型和提供给宿主实验室的人类肌肉活检中，将使用三个特定目标来研究线粒体疾病中肌肉功能缺陷的机制：1)检查线粒体肌病小鼠模型及其对照中分离的骨骼肌细胞中的全局Ca2+处理和力。测量Ca2+处理蛋白在小鼠疾病模型及其对照中的表达。然后，将在线粒体肌病患者的肌肉活检中检查被疾病改变的蛋白质。2)研究线粒体肌病模型中线粒体Ca2+摄取的变化及其与线粒体通透性过渡孔（MPTP）开放的关系。在小鼠模型中鉴定被疾病修饰的MPTP蛋白，随后研究人类样本是否有相同的改变。3)确定小鼠模型中通过药物抑制线粒体Ca2+摄取是否可以停止疾病进展和恢复肌肉功能。这种小鼠模型和人类线粒体肌病患者之间的转化方法将有助于更好地理解损害收缩功能的因素，并开辟新的治疗策略。

DESCRIPTION (provided by applicant): Mitochondrial myopathies are diseases related to dysfunction of the mitochondrial respiratory chain. Defective muscle function is common in mitochondrial disorders and at present effective treatment is lacking. While the knowledge base about genetic mutations as a cause for mitochondrial myopathies is increasing, little is known about how mitochondrial dysfunction actually leads to impaired muscle function. Elucidation of these causative mechanisms will assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases. The ultimate goal of this project is to improve the treatment of mitochondrial myopathies and, in the longer perspective, also treatment of defects in other organs affected by human mitochondrial dysfunction. 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. Three Specific Aims will be used to study the mechanisms underlying the defective muscle function in mitochondrial disorders in specifically designed mouse models and in human muscle biopsies supplied to the host laboratory: 1) Examine global Ca2+ 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 mouse disease models and their controls. Proteins identified as altered by disease will then be examined in muscle biopsies from patients with mitochondrial myopathies. 2) Examine the changes in mitochondrial Ca2+ uptake in models of mitochondrial myopathy and their relation to opening of the mitochondrial permeability transition pore (MPTP). Identify MPTP proteins modified by disease in mouse models and subsequently investigate human samples for the same alterations. 3) Determine whether disease progression can be halted and muscle function recovered by pharmacological inhibition of mitochondrial Ca2+ uptake in mouse models. This translational approach between mouse models and human mitochondrial myopathy patients will lead to a better understanding of factors that impair contractile function and open up new strategies for treatment.