Mechanisms of Mitochondrial Myopathy

线粒体肌病的机制

• 批准号: 8458878
• 负责人: Andres Hernandez
• 金额: $ 4.61万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458878
• 关键词: Affect; Basic Science; Biopsy; Buffers; Calcium; Calsequestrin; Cell Death; Cell physiology; Clinical Research; Complex; Data; Defect; Development; Disease; Disease Progression; Disease model; Functional disorder; Gene Mutation; Goals; Human; Individual; Intervention; Investigation; Knock-out; Laboratories; Lead; Measures; Messenger RNA; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Myopathies; Modeling; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Myopathy; Organ; Outcome; Pathologic Processes; Patients; Pharmacological Treatment; Play; Pore Proteins; Process; Proteins; Quality of life; Respiratory Chain; Rest; Sampling; Sarcoplasmic Reticulum; Skeletal Muscle; Terminally Ill; Testing; base; design; effective therapy; human disease; improved; inhibitor/antagonist; knowledge base; mitochondrial dysfunction; mitochondrial permeability transition pore; mouse model; mtTF1 transcription factor; novel; protein expression; public health relevance; research study; translational approach; treatment strategy; uptake

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.

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原因的知识基础正在增加，但对线粒体功能障碍实际上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，并且从长远来看，还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着关键作用，并且已经提出了治疗这些疾病的新方法。三个特定目的将用于在专门设计的小鼠模型和提供给宿主实验室的人肌肉活检中研究线粒体疾病中肌肉功能缺陷的潜在机制：1）检查线粒体肌病小鼠模型及其对照的分离骨骼肌细胞中的整体Ca2+处理和力。测量小鼠疾病模型及其对照中Ca2+处理蛋白的表达。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)检查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，随后研究人类样本的相同改变。3)在小鼠模型中，确定是否可以通过药理学抑制线粒体Ca2+摄取来阻止疾病进展并恢复肌肉功能。小鼠模型和人类线粒体肌病患者之间的这种转化方法将使人们更好地了解损害收缩功能的因素，并开辟新的治疗策略。