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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）的定义是肌纤维大小和数量的减少，这增加了发病率和发病率