A novel role for oxidized lipid mediators as effectors of muscle atrophy and weakness in aging

氧化脂质介质作为衰老过程中肌肉萎缩和无力效应物的新作用

基本信息

批准号：
10710399
负责人：
HOLLY VAN REMMEN
金额：
$ 56.33万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
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：
2022-09-30 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710399
关键词：
Affect Age Aging Arachidonate 15-Lipoxygenase Arachidonic Acids Atrophic Autophagocytosis Cell Death Cells Data Degradation Pathway Denervation Development Diameter Drug Metabolic Detoxication Effectiveness Elderly Enzymes Generations Goals In Vitro Individual Intervention Knockout Mice Link Lipid Peroxides Measures Mediating Mediator Membrane Mitochondria Modeling Mus Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Muscle Weakness Muscle function Muscular Atrophy Pathway interactions Pattern Phospholipase A2 Phospholipids Population Production Public Health Publishing Quality of life Risk Role Testing Wild Type Mouse Work age related age-related muscle loss design effective intervention experimental study falls frailty healthspan improved in vivo inhibitor insight intervention effect lipid mediator muscle form muscle metabolism nerve supply novel oxidation oxidative damage oxidized lipid pharmacologic prevent protective effect protein degradation proteostasis response sarcopenia successful intervention therapeutic target

项目摘要

Abstract. Sarcopenia, the loss of muscle mass and function with age, is a universal problem in the growing elderly population. To design effective interventions we need to better understand the mechanism(s) responsible for initiation and progression of muscle atrophy and weakness in aging. Studies from our lab and others have shown that loss of innervation is a key driver of muscle atrophy with age. The goal of this proposal is to test a novel hypothesis that bioactive lipid mediators (oxylipins and oxidized phospholipids (oxPL)), are primary effectors for muscle atrophy and weakness. Our hypothesis is strongly supported by our data showing that denervation induces activation of phospholipase A2 (cPLA2), releasing arachidonic acid (AA) from muscle membranes that can promote generation of oxidized lipids, either non-enzymatically or via 12/15 lipoxygenase (Alox15) dependent generation. We have also shown that denervation-induced muscle loss is decreased when AA release and oxidized lipids are blocked by inhibition of cPLA2 or Alox15, or by scavenging of LOOH using liproxstatin-1 or Gpx4Tg mice, thus supporting oxPL/oxylipins as a critical mechanistic link between denervation and muscle wasting. However, the mechanisms by which oxPL/oxylipins cause muscle atrophy have not been defined. Based on previously identified targets of these lipid mediators, we are specifically testing the hypothesis that oxPL/oxylipins induced by denervation cause damage to membranes, promote mitochondrial changes and activate proteolytic and cell death pathways to induce age-related muscle atrophy. In Aim 1, we will define the effect of modulating oxylipins on atrophy related targets by inhibiting generation of oxPL/oxylipins (using cPLA2KO and Alox15KO mice) and by altering reduction of lipid hydroperoxides (using Gpx4/Tg and muscle specific Gpx4KO mice and treatment with liproxstatin-1) on membrane oxidative damage, mitochondrial function, muscle degradative and cell death pathways and muscle mass after denervation. These experiments will identify the primary oxylipins produced in denervated muscle and identify the critical targets of oxylipins that lead to muscle atrophy and weakness. In Aim 2, we will measure the effect of key oxylipins identified in Aim 1 in vitro in C2C12 muscle cells on oxidative damage, mitochondrial function, protein degradation pathways and muscle fiber diameter. These experiments will provide new information on the effect of specific oxylipins on muscle metabolism and mitochondrial function. Finally, in Aim 3, we will test whether inhibiting oxylipin generation in vivo in muscle specific Alox15KO mice or reducing levels of lipid hydroperoxides (LOOH) in mice with elevated levels of Gpx4 expression can protect against age-related muscle atrophy in vivo in aging mice. We predict that reduced generation of oxPL/oxylipins and enhanced detoxification of lipid hydroperoxides (LOOH) will modify the atrophy targets outlined in Aim 1, reducing muscle atrophy and weakness in aging mice. Overall, these experiments will be the first to investigate the role of oxylipins in sarcopenia and their potential as a target for intervention in muscle loss and weakness.

抽象的。肌肉减少症，即肌肉质量和功能随着年龄的增长而丧失，是成长中的一个普遍问题。老年人口。为了设计有效的干预措施，我们需要更好地理解负责的机制用于衰老过程中肌肉萎缩和无力的开始和进展。我们实验室和其他实验室的研究表明研究表明，随着年龄的增长，神经支配的丧失是肌肉萎缩的关键驱动因素。该提案的目标是测试一个新的假设认为生物活性脂质介质（氧脂质和氧化磷脂（oxPL））是肌肉萎缩和无力的主要效应器。我们的假设得到了数据的有力支持显示去神经支配诱导磷脂酶 A2 (cPLA2) 的激活，释放花生四烯酸 (AA) 可以通过非酶促或通过 12/15 促进氧化脂质生成的肌肉膜脂氧合酶 (Alox15) 依赖性世代。我们还表明，去神经引起的肌肉损失是当通过抑制 cPLA2 或 Alox15 或通过清除来阻断 AA 释放和氧化脂质时，该值会降低使用 liproxstatin-1 或 Gpx4Tg 小鼠进行 LOOH 的分析，从而支持 oxPL/oxylipins 作为关键的机制联系去神经支配和肌肉萎缩之间。然而，oxPL/oxylipins 引起肌肉损伤的机制萎缩尚未定义。根据之前确定的这些脂质介质的靶标，我们特别检验去神经诱导的 oxPL/oxylipins 对膜造成损伤的假设，促进线粒体变化并激活蛋白水解和细胞死亡途径以诱导年龄相关肌肉萎缩。在目标 1 中，我们将通过抑制来定义调节氧脂素对萎缩相关靶点的影响 oxPL/oxylipins 的产生（使用 cPLA2KO 和 Alox15KO 小鼠）并通过改变脂质的减少氢过氧化物（使用 Gpx4/Tg 和肌肉特异性 Gpx4KO 小鼠并用 liproxstatin-1 治疗）膜氧化损伤、线粒体功能、肌肉降解和细胞死亡途径以及肌肉去神经后肿块。这些实验将鉴定去神经肌肉中产生的初级氧脂质并确定氧脂素导致肌肉萎缩和无力的关键靶标。在目标 2 中，我们将测量 Aim 1 中鉴定的关键氧脂素对 C2C12 肌细胞体外氧化损伤、线粒体的影响功能、蛋白质降解途径和肌纤维直径。这些实验将提供新的有关特定氧脂素对肌肉代谢和线粒体功能影响的信息。最后，在目标 3、我们将测试是否抑制肌肉特异性Alox15KO小鼠体内的氧脂素生成或降低水平 Gpx4 表达水平升高的小鼠体内的脂质过氧化氢 (LOOH) 可以预防年龄相关的衰老小鼠体内肌肉萎缩。我们预测 oxPL/oxylipins 的生成减少并增强脂质过氧化氢 (LOOH) 的解毒将改变目标 1 中概述的萎缩目标，减少肌肉衰老小鼠的萎缩和虚弱。总的来说，这些实验将是第一个研究氧脂质作用的实验肌肉减少症及其作为干预肌肉损失和无力的目标的潜力。