LOOH-induced muscle atrophy with age

随着年龄的增长，LOOH 引起的肌肉萎缩

• 批准号: 10382124
• 负责人: Micah J Drummond
• 金额: $ 53.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/10382124
• 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

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 骨骼肌群的维持对健康衰老至关重要，对生活质量起着重要作用。 年龄引起的骨骼肌萎缩(肌萎缩症)不仅降低了活动能力，而且增加了 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 在日益久坐不动和老龄化的人口中，针对肌肉质量减轻的药物疗法并不适用 是存在的。活性氧物种(ROS)可能通过加速蛋白质分解和抑制而导致肌肉萎缩 蛋白质合成。然而，ROS指的是细胞信号巨大的自由基分子的集合， 目前还不清楚氧化应激的哪些下游后果导致了 随着年龄增长或停用而出现的肌肉质量和功能。在此应用程序中，我们将测试我们的假设 脂类ROS(LOOH)通过加速自噬/溶酶体依赖蛋白促进肌肉萎缩 退化。1)细胞LOOH被磷脂氢过氧化物酶(Gpx4)中和，阻止其 积累和降解形成活性脂醛。我们将确定中和是否 N-乙酰肌肽治疗(脂醛清除剂)的LOOH将抑制衰老和/或停用诱导 骨骼肌萎缩。2)抑制多不饱和脂肪酸(PUFA)的掺入 抑制溶血磷脂酰胆碱酰基转移酶-3(LPCAT3)可防止LOOH诱导的细胞死亡。我们会 研究LPCAT3缺失是否可以保护小鼠免受肌肉萎缩的影响，并进行亚细胞流动组学研究 研究氧化应激过程中LPCAT3产物在细胞内的去向。3)Gpx4缺失增加蛋白质 通过加速溶酶体降解来降解。我们将检验我们的假设，LOOH增压 自噬机械通过其与LC3的脂化作用。