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：
10552003
负责人：
Micah J Drummond
金额：
$ 53.73万
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/10552003
关键词：
ATG3 gene Acceleration Acyltransferase Affect Age Aging Aldehydes Atrophic Autophagocytosis Autophagosome Carboxy-Lyases Cardiovascular Diseases Cell Death Induction Cell Size Clinical Collection Data Diameter Enzymes Hydroxyl Radical In Vitro Knowledge 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 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 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 pharmacologic 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.

项目概要维持骨骼肌质量对于健康老龄化至关重要，并且对生活质量起着重要作用。年龄引起的骨骼肌萎缩（肌少症）不仅会降低活动能力，还会增加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老龄化的人口中，针对肌肉质量损失的药物疗法并不有效存在。活性氧（ROS）可能通过加速蛋白水解和抑制来诱导肌肉萎缩蛋白质合成。然而，ROS 是指细胞信号巨大的自由基分子的集合，目前尚不清楚氧化应激的哪些下游后果导致了随着年龄或废弃而出现的肌肉质量和功能。在此应用中，我们将检验我们的假设脂质 ROS (LOOH) 通过加速自噬/溶酶体依赖性蛋白促进肌肉萎缩降解。 1) 细胞LOOH被磷脂氢过氧化物酶(GPx4)中和，防止其发生积累和降解形成反应性脂质醛。我们将确定是否中和 LOOH 通过 N-乙酰肌肽处理（脂醛清除剂）将抑制衰老和/或废用引起的骨骼肌萎缩。 2) 抑制多不饱和脂肪酸（PUFA）的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，并进行亚细胞通量组学检查氧化应激期间 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。我们将检验 LOOH 增压的假设通过 LC3 脂化来实现自噬机制。