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: 10348145
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348145
• 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; Chromosomes; Chronic; Consensus; Cytosol; D4Z4; Defect; Denervation; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Equilibrium; FRG1 gene; Facioscapulohumeral Muscular Dystrophy; Genes; Heart failure; Homeostasis; Inner mitochondrial membrane; Lead; Longevity; Malignant Neoplasms; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Myocardium; Myopathy; Neuromuscular Diseases; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathogenicity; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Production; Protein Biosynthesis; Protein Import; Protein Isoforms; Proteins; Respiration; Rett Syndrome; Role; SLC25A4 gene; Signal Transduction; Stress; Structure; Testing; Transgenic Mice; Triage; Validation; aged; base; 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; transcriptomics

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.

肌肉浪费（或萎缩）是由肌纤维的大小，数量和强度降低来定义的。它发生在衰老中， 肌肉废弃，神经支配，癌症，艾滋病，糖尿病和心力衰竭，会增加脆弱，发病率 和死亡率。在生理条件下，肌纤维大小通过蛋白质之间的平衡维持 合成和降解。在各种萎缩条件下，蛋白质量如何不平衡 理解。线粒体功能障碍已提出有助于进行性肌肉萎缩。最多 研究集中在线粒体在能量产生，氧化应激和凋亡中的作用。 然而，最近的研究表明，大量的生物能缺乏和氧化应激是 不足以引起肌纤维收缩和进行性肌肉浪费。如果线粒体应力导致 肌肉浪费，它必须涉及一种新型机制。我们最近生成了一个转基因小鼠 中度过表达ANT1的线，腺嘌呤核苷酸易位酶的肌肉/心脏同工型 参与线粒体内膜（IMM）内膜的ATP/ADP交换，以建模 最常见的肌肉疾病被称为Faciosculohumeral肌肉营养不良（FSHD）。我们发现 ANT1-转基因小鼠减少了肌纤维的大小并逐渐失去肌肉质量。我们的初步 研究支持这样的观念，即除了中等生物能缺陷外，ANT1伯爵表达 细胞质中的蛋白质应激。我们假设ANT1超载可能会干扰蛋白质的进口和 导致线粒体前体过度累积应力（MPO），这是一种新的线粒体诱导的应力 其特征是细胞质中未蒙受的蛋白质过多。我们还建议 蛋白抑制对MPO的适应可能会长期降低蛋白质合成并增加蛋白质 退化，最终导致肌肉浪费。在此应用程序中，我们将通过 提出以下特定目标。 （1）我们将测试中等ANT1过表达是否足够 诱导细胞质中的蛋白质应激。 （2）我们将确定对对 未刺激的线粒体蛋白的分类。 （3）我们将测试ANT1诱导的肌肉的假设 萎缩是由蛋白质合成和/或蛋白酶体和自噬活性增加的萎缩引起的， 触发是对MPO的压力反应。该项目的成功可能导致发现小说 线粒体影响肌肉质量稳态的机制。结果可能是直接的 对理解几种涉及ANT1过表达的疾病的影响，包括FSHD， 扩张的心肌病和RETT综合征。最后，小鼠中MPO模型的验证可能具有 对影响蛋白质进口的其他线粒体疾病的理解的广泛意义。