Mechanisms of Mitochondrial Myopathy

描述(申请人提供)：线粒体肌病是与线粒体呼吸链功能障碍有关的疾病。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。虽然关于基因突变是线粒体肌病的原因的知识库正在增加，但关于线粒体功能障碍实际上是如何导致肌肉功能受损的知之甚少。这些致病机制的阐明将有助于药物治疗的发展，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进线粒体肌病的治疗，从更长远的角度来看，也是为了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(Ca~(2+))处理的改变在收缩功能障碍中起关键作用，并推测了一种治疗这些疾病的新方法。有三个特定的目的将被用来研究线粒体疾病中肌肉功能缺陷的机制，在专门设计的小鼠模型和提供给东道主实验室的人类肌肉活检中：1)检测线粒体肌病小鼠模型和对照小鼠分离的骨骼肌细胞中整体钙的处理和作用力。检测钙调节蛋白在小鼠疾病模型及其对照中的表达。被确认为疾病改变的蛋白质将在线粒体肌病患者的肌肉活组织检查中进行检查。2)检测线粒体肌病模型中线粒体钙摄取的变化及其与线粒体通透性转换孔(MPTP)开放的关系。在小鼠模型中识别疾病修饰的MPTP蛋白，并随后研究人类样本中相同的变化。3)确定是否可以通过药物抑制小鼠线粒体钙摄取来阻止疾病进展和恢复肌肉功能。这种在小鼠模型和人类线粒体肌病患者之间进行转换的方法将有助于更好地理解损害收缩功能的因素，并为治疗开辟新的策略。 公共卫生相关性：肌肉功能缺陷在线粒体肌病患者中很常见。虽然关于基因突变是线粒体肌病的原因的知识库正在增加，但关于线粒体功能障碍实际上是如何导致肌肉功能受损的知之甚少。拟议的项目旨在阐明致病机制，并协助开发可提高这些疾病患者生活质量的药物治疗方法。

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. PUBLIC HEALTH RELEVANCE: Defective muscle function is common in people with mitochondrial myopathies. 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. The proposed project aims to elucidate causative mechanisms and to assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases.