Mechanism of mitochondria-induced proteostatic signaling and progressive muscle atrophy during aging.

衰老过程中线粒体诱导的蛋白质抑制信号传导和进行性肌肉萎缩的机制。

基本信息

批准号：
10825174
负责人：
Nicholas Brennan
金额：
$ 5.27万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2027-09-13
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10825174
关键词：
Ablation Acute Adenine Nucleotide Translocase Affect Aging Amino Acids Apoptosis Attenuated Autophagocytosis Biochemical Bioenergetics Biological Assay Cell Death Cell Death Induction Cessation of life Chronic Clinical Cytosol Data Defect Disease Dual-Energy X-Ray Absorptiometry Equilibrium Fellowship Goals Histologic Inner mitochondrial membrane Knowledge Mass Spectrum Analysis Measurement Mediating Membrane Proteins Mitochondria Mitochondrial Diseases Mitochondrial Proteins Molecular Morbidity - disease rate Mus Muscle Muscular Atrophy Myopathy NADH Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Peptide Hydrolases Phosphorylation Phosphotransferases Play Process Production Protein Biosynthesis Protein Import Proteins Quality of life Reactive Oxygen Species Repression Respiration Role SLC25A4 gene Scanning Signal Transduction Skeletal Muscle Starvation Stress Stress Response Signaling Testing Tissues Transgenic Mice Translations aged biological adaptation to stress in vivo insight mitochondrial dysfunction mortality mouse model multicatalytic endopeptidase complex muscle aging muscle form muscle stress novel novel therapeutics overexpression preservation protein degradation proteostasis response sarcopenia skeletal muscle wasting stressor transcriptome sequencing wasting

项目摘要

Muscle atrophy (or wasting) is defined by reduced myofiber size and number, which increases morbidity and mortality and decreases quality of life. One of the mechanisms of muscle atrophy is the loss of proteostatic balance. When protein degradation exceeds synthesis, protein content is decreased to reduce myofiber size and muscle mass. How the balance between protein synthesis and degradation is disturbed in diseased and aged skeletal muscle in unknown. Mitochondrial dysfunction plays an important role in skeletal muscle atrophy under many disease conditions and during normative aging, with the underlying mechanism remaining poorly understood. Perturbations in oxidative phosphorylation and the subsequent increase in reactive oxygen species production, collectively termed “bioenergetic defects”, have been proposed to drive muscle loss. However, accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative stress are insufficient to cause muscle wasting. Therefore, if mitochondrial dysfunction does indeed result in muscle loss, it may involve bioenergetically independent factors. The Chen lab recently found that various forms of mitochondrial damage can reduce mitochondrial protein import. This causes proteostatic stress in the cytosol, termed mitochondrial Precursor Overaccumulation Stress (mPOS), followed by global remodeling of proteostasis. We recently generated a transgenic mouse line that moderately overexpresses the mitochondrial inner membrane protein, Ant1. We found that Ant1-induced mitochondrial protein import stress causes progressive muscle atrophy, accompanied by reduction of mitochondrial respiration. However, whether muscle atrophy is caused by bioenergetic deficiency or bioenergetic-independent stressors remains unknown. Interestingly, RNA-seq analysis revealed a robust activation of the integrated stress response (ISR), which in turn represses global protein synthesis and activates autophagy. ISR activation is commonly found in tissues derived from patients with mitochondrial disease. Using this unique mouse model, we propose to determine the molecular mechanisms of mitochondria-induced muscle atrophy and ISR activation. In Aim 1, we will determine the mechanism by which mitochondrial protein import stress induces muscle wasting. In Aim 2, we will determine whether ISR activation protects skeletal muscle from myofiber death and myopathy in the setting of mPOS. The long-term goal of this project is to understand how bioenergetics-independent mitochondrial stress signaling promotes chronic muscle wasting in normative and non-normative aging. The results of this application may help establish a bioenergetics-independent pathway for treating mitochondria-induced muscle disease and possibly sarcopenia.

肌肉萎缩（或消瘦）是指肌纤维尺寸和数量减少，这会增加发病率和死亡率和生活质量下降是肌肉萎缩的机制之一。当蛋白质降解超过合成时，蛋白质含量就会减少，从而减少肌纤维的尺寸。和肌肉质量。蛋白质合成和降解之间的平衡如何在患病和衰老的骨骼肌线粒体功能障碍在骨骼肌萎缩中起着重要作用。在许多疾病条件下和正常衰老过程中，潜在机制仍然很差了解氧化磷酸化的扰动以及随后活性氧的增加。物种产生统称为“生物能缺陷”，有人提出会导致肌肉损失。然而，越来越多的证据表明，大量的生物能缺乏和氧化因此，如果线粒体功能障碍确实导致肌肉萎缩。肌肉损失，可能涉及生物能量独立因素，陈实验室最近发现，多种因素。线粒体损伤会减少线粒体蛋白质的输入，从而导致蛋白质稳态应激。细胞质，称为线粒体前体过度积累应激（mPOS），然后进行全局重塑我们最近产生了一种适度过度表达线粒体的转基因小鼠品系。我们发现Ant1诱导的线粒体蛋白输入应激会导致内膜蛋白Ant1。进行性肌肉萎缩，同时伴有线粒体呼吸功能的减少，但无论是肌肉。萎缩是由生物能缺乏或生物能独立的应激源引起的仍然未知。 RNA-seq 分析揭示了整合应激反应 (ISR) 的强烈激活，这在转角抑制整体蛋白质合成并激活自噬，这在组织中很常见。来自患有线粒体疾病的患者，我们建议使用这种独特的小鼠模型来确定在目标 1 中，我们将确定线粒体诱导的肌肉萎缩和 ISR 激活的分子机制。在目标 2 中，我们将研究线粒体蛋白输入应激导致肌肉萎缩的机制。确定 ISR 激活是否可以保护骨骼肌免受肌纤维死亡和肌病的影响 mPOS 该项目的长期目标是了解生物能量独立的线粒体应激如何发生。信号传导会促进正常和非正常衰老过程中的慢性肌肉萎缩。应用可能有助于建立一种独立于生物能学的途径来治疗线粒体诱导的肌肉疾病和可能的肌肉减少症。