LOOH-induced muscle atrophy with age

随着年龄的增长，LOOH 引起的肌肉萎缩

基本信息

批准号：
10588970
负责人：
Micah J Drummond
金额：
$ 7.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588970
关键词：
ATG3 gene Acyltransferase Affect Age Aging Aldehydes Atrophic Autophagocytosis Autophagosome Caliber Carboxy-Lyases Cardiovascular Diseases Cell Death Cell Size Clinical Collection Data Enzymes Hydroxyl Radical In Vitro Knowledge Lead Lecithin Lipid Peroxides Lipids Lysophosphatidylcholines Lysosomes Maintenance Medical Membrane Metabolic Diseases Mitochondria Modeling Molecular Mus Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Nature Oxidative Stress Pathway interactions Pharmacology Phosphatidylethanolamine Phosphatidylserines Phospholipids Play Polyunsaturated Fatty Acids Population Production Protein Biosynthesis Proteolysis Quality of life Reaction Reactive Oxygen Species Role Signal Transduction Skeletal Muscle Source Stress Testing Therapeutic Water aging population base cell injury cell type diet and exercise experimental study glutathione peroxidase healthy aging in vivo inhibition of autophagy muscle aging muscle form muscle strength novel strategies overexpression pi bond prevent protein degradation sarcopenia sedentary skeletal muscle wasting

项目摘要

Project Summary Maintenance of skeletal muscle mass is essential for healthy aging and plays a significant role in quality of life. Age-induced skeletal muscle atrophy (sarcopenia) not only reduces mobility but also increases the propensity to develop metabolic and cardiovascular diseases. Although skeletal muscle atrophy has broad clinical impact in the increasingly sedentary and aging population, a pharmacologic therapy for muscle mass loss does not exist. Reactive oxygen species (ROS) likely induce muscle atrophy by accelerating proteolysis and depressing protein synthesis. However, ROS refers to a collection of radical molecules whose cellular signals are vast, and it is unclear which of the downstream consequences of oxidative stress are responsible for the loss of muscle mass and function that occurs with age or disuse. In this application, we will test our hypothesis that lipid ROS (LOOH) promotes muscle atrophy through accelerating autophagy/lysosome-dependent protein degradation. 1) Cellular LOOH is neutralized by phospholipid hydroperoxidase (GPx4), preventing its accumulation and degradation to form reactive lipid aldehydes. We will determine whether neutralization of LOOH by N-acetylcarnosine treatment (lipid aldehyde scavenger) will suppress age and/or disuse-induced skeletal muscle atrophy. 2) Suppression of polyunsaturated fatty acid (PUFA) incorporation by lysophosphatidylcholine acyltransferase-3 (LPCAT3) inhibition prevents LOOH-induced cell death. We will investigate whether LPCAT3 deletion can protect mice from muscle atrophy, and perform subcellular fluxomics to examine intracellular fate of LPCAT3 product during oxidative stress. 3) GPx4 deletion increases protein degradation by accelerating lysosomal degradation. We will test our hypothesis that LOOH supercharges autophagic machinery by its lipidation with LC3.

项目摘要维持骨骼肌质量对于健康衰老至关重要，并且在生活质量中起着重要作用。年龄引起的骨骼肌萎缩（肌肉减少症）不仅降低了迁移率，而且还增加了倾向发展代谢和心血管疾病。尽管骨骼肌萎缩具有广泛的临床影响在日益久坐和衰老的人口中，肌肉质量损失的药理学疗法不会存在。活性氧（ROS）可能通过加速蛋白水解并降低来诱导肌肉萎缩蛋白质合成。但是，ROS是指一组细胞信号的自由基分子的集合，目前尚不清楚氧化应激的下游后果是导致损失的原因肌肉质量和功能随着年龄的增长而发生。在此应用程序中，我们将测试我们的假设脂质ROS（LOOH）通过加速自噬/溶酶体依赖性蛋白来促进肌肉萎缩降解。 1）细胞LooH被磷脂氢过氧化物酶（GPX4）中和，以防止其积累和降解形成反应性脂质醛。我们将确定中和是否是否通过N-乙酰肉推氨酸处理（脂质醛清除剂）将抑制年龄和/或废弃诱导的骨骼肌萎缩。 2）抑制多不饱和脂肪酸（PUFA）掺入溶血磷脂酰胆碱酰基转移酶-3（LPCAT3）抑制可防止LooH诱导的细胞死亡。我们将研究LPCAT3缺失是否可以保护小鼠免受肌肉萎缩的侵害，并执行亚细胞通量学在氧化应激期间检查LPCAT3产物的细胞内命运。 3）GPX4缺失增加蛋白质通过加速溶酶体降解来降解。我们将测试Looh增压的假设自噬机械通过LC3脂质化。