Mechanism of Mitochondria-induced Progressive Muscle Wasting

线粒体诱导进行性肌肉萎缩的机制

基本信息

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
项目类别：
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

项目摘要

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）是指肌纤维尺寸、数量和强度减少。它发生在衰老过程中，肌肉废用、去神经支配、癌症、艾滋病、糖尿病和心力衰竭，这些都会增加虚弱和发病率和死亡率。在生理条件下，肌纤维大小是通过蛋白质之间的平衡来维持的合成和降解。各种萎缩条件下蛋白质稳态如何失衡尚不清楚明白了。线粒体功能障碍已被认为会导致进行性肌肉萎缩。最多研究重点是线粒体在能量产生、氧化应激和细胞凋亡中的作用。然而，最近的研究表明，相当程度的生物能缺乏和氧化应激不足以引起肌纤维收缩和进行性肌肉萎缩。如果线粒体应激导致肌肉萎缩，它必须涉及一种新的机制。我们最近培育了一只转基因小鼠中度过表达 Ant1 的品系，Ant1 是腺嘌呤核苷酸转位酶的肌肉/心脏亚型参与跨线粒体内膜 (IMM) 的 ATP/ADP 交换，以模拟其中之一最常见的肌肉疾病称为面肩肱型肌营养不良症（FSHD）。我们发现 ANT1 转基因小鼠的肌纤维尺寸减小，肌肉质量逐渐减少。我们的初步研究支持这样的观点：除了中度生物能缺陷之外，ANT1 过度表达还会导致细胞质中的蛋白质稳态应激。我们假设 Ant1 超载可能会干扰蛋白质的输入和引起线粒体前体过度积累应激（mPOS），一种新型线粒体诱导应激其特征是细胞质中未输入的蛋白质过度积累。我们还建议对 mPOS 的蛋白质抑制适应可能会长期减少蛋白质合成并增加蛋白质退化，最终导致肌肉萎缩。在此应用程序中，我们将通过以下方式测试这些假设提出以下具体目标。 (1) 我们将测试适度的ANT1过度表达是否足够诱导细胞质中的蛋白质稳态应激。 (2) 我们将确定对于对未输入的线粒体蛋白进行分类。 (3) 我们将检验 Ant1 诱导肌肉的假设萎缩是由于蛋白质合成减少和/或蛋白酶体和自噬活性增加造成的，作为对 mPOS 的压力反应而触发。该项目的成功可能会导致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 ANT1 过度表达的几种疾病的影响，包括 FSHD、扩张型心肌病和雷特综合征。最后，mPOS 模型在小鼠身上的验证可以对于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

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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