Mechanism of Mitochondria-induced Progressive Muscle Wasting

线粒体诱导进行性肌肉萎缩的机制

• 批准号: 10539303
• 负责人: Xin Jie Chen
• 金额: $ 39.67万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539303
• 关键词: 1 year old; ATP Synthesis Pathway; Acquired Immunodeficiency Syndrome; Acute; Adenine Nucleotide Translocase; Affect; Aging; Animals; Apoptosis; Atrophic; Autophagocytosis; Bioenergetics; Cells; Cessation of life; Chromosome 4; Chronic; Consensus; Cytoprotection; Cytosol; D4Z4; Defect; Denervation; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Equilibrium; FRG1 gene; Facioscapulohumeral Muscular Dystrophy; Genes; Heart; Heart failure; Homeostasis; Inner mitochondrial membrane; Longevity; Malignant Neoplasms; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Muscular Dystrophies; Myopathy; Neuromuscular Diseases; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Production; Protein Biosynthesis; Protein Import; Protein Isoforms; Proteins; Respiration; Rett Syndrome; Role; SLC25A4 gene; Signal Induction; Signal Transduction; Stress; Structure; Testing; Transgenic Mice; Triage; Validation; aged; biological adaptation to stress; frailty; interest; mitochondrial dysfunction; mortality; mouse model; muscle form; novel; overexpression; prevent; protein aggregation; protein degradation; protein misfolding; proteostasis; sarcopenia; success; therapy development; tool; transcriptomic profiling

Muscle wasting (or atrophy) is defined by reduced myofiber size, number and strength. It occurs in aging, muscle disuse, denervation, cancer, AIDS, diabetes and cardiac failure, which increases frailty, morbidity and mortality. Under physiological conditions, myofiber size is maintained by a balance between protein synthesis and degradation. How proteostasis is unbalanced under various atrophying conditions is poorly understood. Mitochondrial dysfunction has been proposed to contribute to progressive muscle atrophy. Most studies have been focused on the role of mitochondria in energy production, oxidative stress and apoptosis. However, recent studies showed that considerable levels of bioenergetic deficiency and oxidative stress are not sufficient to cause myofiber shrinkage and progressive muscle wasting. If mitochondrial stress causes muscle wasting, it would have to involve a novel mechanism. We recently generated a transgenic mouse line that moderately overexpresses Ant1, the muscle/heart isoform of adenine nucleotide translocase involved in ATP/ADP exchange across the inner membrane of mitochondria (IMM), to model one of the most common muscle diseases known as Facioscapulohumeral Muscular Dystrophy (FSHD). We found that the ANT1-transgenic mice have reduced myofiber size and progressively lose muscle mass. Our preliminary studies support the idea that, in addition to moderate bioenergetic defect, ANT1-overexpression causes proteostatic stress in the cytosol. We hypothesize that Ant1 overloading may disturb protein import and cause mitochondrial Precursor Overaccumulation Stress (mPOS), a novel mitochondria-induced stress characterized by the overaccumulation of unimported proteins in the cytosol. We also propose that proteostatic adaptation to mPOS may chronically reduce protein synthesis and increase protein degradation, which ultimately leads to muscle wasting. In this application, we will test these hypotheses by proposing the following specific aims. (1) We will test whether moderate ANT1 overexpression is sufficient to induce proteostatic stress in the cytosol. (2) We will identify cytosolic pathways that are important for the triage of unimported mitochondrial proteins. (3) We will test the hypothesis that Ant1-induced muscle atrophy results from reduced protein synthesis and/or increased proteasomal and autophagy activities, triggered as stress responses to mPOS. Success of the project may lead to the discovery of a novel mechanism by which mitochondria affect muscle mass homeostasis. The results could have direct implications for the understanding of several diseases that involve ANT1 overexpression, including FSHD, dilated cardiomyopathy and Rett syndrome. Finally, the validation of the mPOS model in mice could have broad implications for the understanding of other mitochondrial disorders that affect protein import.

肌肉萎缩（或萎缩）的定义是肌纤维大小、数量和强度减少。它发生在衰老， 肌肉废用，去神经支配，癌症，艾滋病，糖尿病和心力衰竭，这增加了虚弱，发病率 and mortality.在生理条件下，肌纤维的大小是由蛋白质之间的平衡来维持的。 合成和降解。在各种萎缩条件下，蛋白质稳态是如何失衡的， 明白线粒体功能障碍被认为是导致进行性肌肉萎缩的原因。最 研究集中在线粒体在能量产生、氧化应激和细胞凋亡中的作用。 然而，最近的研究表明，相当程度的生物能量缺乏和氧化应激是 不足以引起肌纤维收缩和进行性肌肉萎缩。如果线粒体压力导致 肌肉萎缩，它必须涉及一种新的机制。我们最近培育了一只转基因老鼠 中度过表达Ant 1（腺嘌呤核苷酸移位酶的肌肉/心脏同种型）的细胞系 参与线粒体内膜（IMM）的ATP/ADP交换，以模拟其中一种 最常见的肌肉疾病称为面肩肱肌营养不良症（FSHD）。我们发现 ANT 1转基因小鼠肌纤维尺寸减小，肌肉质量逐渐减少。我们的初步 研究支持这样的观点，即除了中度生物能量缺陷，ANT 1过表达导致 细胞质中的蛋白抑制应激。我们假设Ant 1超载可能会干扰蛋白质的输入， 引起线粒体前体过度积累应激（mPOS），一种新的线粒体诱导的应激 以胞质溶胶中非输入蛋白质的过度积累为特征。我们亦建议 对mPOS的蛋白质抑制性适应可慢性减少蛋白质合成并增加蛋白质合成。 退化，最终导致肌肉萎缩。在本申请中，我们将通过以下方式检验这些假设： 提出以下具体目标。(1)我们将测试适度的ANT 1过表达是否足以 以诱导胞质溶胶中的蛋白质抑制应激。(2)我们将确定胞质途径，这是重要的， 非输入线粒体蛋白的分类。(3)我们将测试Ant 1诱导的肌肉 萎缩由蛋白质合成减少和/或蛋白酶体和自噬活性增加引起， 是对mPOS的应激反应该项目的成功可能会导致一部小说的发现 线粒体影响肌肉质量稳态的机制。结果可能会直接 对理解涉及ANT 1过表达的几种疾病的意义，包括FSHD， 扩张型心肌病和雷特综合征。最后，mPOS模型在小鼠中的验证可能已经 对理解影响蛋白质输入的其他线粒体疾病具有广泛的意义。

项目成果

A Gravity-Fed Transcardial Perfusion Method for Histologic Analysis of the Mouse Central Nervous System.

• DOI: 10.3791/63386
• 发表时间: 2022-01-21
• 期刊: Journal of visualized experiments : JoVE
• 作者: Rana A;Massa PT;Chen XJ
• 通讯作者: Chen XJ

Cytosolic adaptation to mitochondria-induced proteostatic stress causes progressive muscle wasting.

• DOI: 10.1016/j.isci.2021.103715
• 发表时间: 2022-01-21
• 期刊: iScience
• 影响因子: 5.8
• 作者: Wang X;Middleton FA;Tawil R;Chen XJ
• 通讯作者: Chen XJ

Mitochondrial protein import clogging as a mechanism of disease.

• DOI: 10.7554/elife.84330
• 发表时间: 2023-05-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Coyne LP;Wang X;Song J;de Jong E;Schneider K;Massa PT;Middleton FA;Becker T;Chen XJ
• 通讯作者: Chen XJ