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。

• 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
• 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

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）的定义是肌纤维大小和数量减少，这增加了发病率， 死亡率和生活质量下降。肌肉萎缩的机制之一是蛋白质抑制的丧失， 平衡当蛋白质降解超过合成时，蛋白质含量减少以减小肌纤维尺寸 和肌肉质量。蛋白质合成和降解之间的平衡是如何在患病和 骨骼肌老化情况不明。线粒体功能障碍在骨骼肌萎缩中起重要作用 在许多疾病条件下和正常老化期间，潜在机制仍然很差 明白氧化磷酸化的扰动和随后的活性氧增加 已提出物种产生（统称为“生物能缺陷”）驱动肌肉损失。 然而，越来越多的证据表明，大量的生物能量缺乏和氧化 压力不足以引起肌肉萎缩。因此，如果线粒体功能障碍确实导致 肌肉损失，它可能涉及生物能量独立的因素。Chen实验室最近发现， 线粒体损伤的形式可以减少线粒体蛋白质的输入。这会导致细胞内的蛋白抑制应激， 细胞质，称为线粒体前体过度积累应激（mPOS），随后是全球重塑 蛋白质稳态我们最近培育了一种转基因小鼠品系， 内膜蛋白Ant 1。我们发现Ant 1诱导的线粒体蛋白输入应激导致了 进行性肌肉萎缩，伴有线粒体呼吸减少。无论肌肉 萎缩是由生物能量缺乏或生物能量独立的应激源引起的，这仍然是未知的。 有趣的是，RNA-seq分析揭示了整合应激反应（ISR）的强烈激活，这在 turn抑制整体蛋白质合成并激活自噬。ISR激活通常在组织中发现 来源于线粒体疾病患者。使用这种独特的小鼠模型，我们建议确定 研究表明，这是一种新的肌萎缩和ISR激活的分子机制。在目标1中，我们将确定 线粒体蛋白输入应激诱导肌肉萎缩的机制。在目标2中，我们将 确定ISR激活是否保护骨骼肌免于肌纤维死亡和肌病， mPOS。该项目的长期目标是了解生物能量无关的线粒体应激是如何 信号传导促进正常和非正常老化中的慢性肌肉消耗。的结果 应用可能有助于建立一种治疗线粒体诱导的肌肉的生物能量独立途径 可能还有肌肉减少症