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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。肌肉减少症，随着年龄的增长肌肉质量和功能的丧失，是一个普遍的问题，老年人口。为了设计有效的干预措施，我们需要更好地了解负责的机制用于衰老中肌肉萎缩和虚弱的起始和进展。我们实验室和其他机构的研究表明，显示神经支配的丧失是随着年龄增长肌肉萎缩的关键驱动因素。这项提案的目的是测试一种新的假设，即生物活性脂质介质（氧脂和氧化磷脂（oxPL）），肌肉萎缩和虚弱的主要效应器。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（cPLA 2）的活化，从细胞中释放花生四烯酸（AA），肌肉膜可以促进氧化脂质的产生，无论是非酶促还是通过12/15 脂氧合酶（Alox 15）依赖性生成。我们还表明，去神经诱导的肌肉损失是当AA释放和氧化脂质通过抑制cPLA 2或Alox 15或通过清除使用livestatin-1或Gpx 4 Tg小鼠的LOOH，从而支持oxPL/氧化脂质作为关键的机制联系去神经支配和肌肉萎缩之间的联系然而，oxPL/氧脂素引起肌肉收缩的机制是，萎缩尚未得到定义。基于先前确定的这些脂质介质的靶点，我们特别检验由去神经支配诱导的oxPL/oxlipins引起膜损伤的假设，促进线粒体变化，激活蛋白水解和细胞死亡途径，肌肉萎缩在目的1中，我们将定义通过抑制氧化脂质对萎缩相关靶点的调节作用。 oxPL/氧脂蛋白的产生（使用cPLA 2KO和Alox 15 KO小鼠）和通过改变脂质的减少氢过氧化物（使用Gpx 4/Tg和肌肉特异性Gpx 4KO小鼠，并用利司他汀-1处理）膜氧化损伤，线粒体功能，肌肉降解和细胞死亡途径和肌肉去神经后的肿块。这些实验将鉴定去神经肌肉中产生的主要氧脂素并确定导致肌肉萎缩和虚弱的氧脂素的关键目标。在目标2中，我们将测量在C2 C12肌细胞中，Aim 1中鉴定的关键氧脂素对氧化损伤、线粒体功能、蛋白质降解途径和肌纤维直径。这些实验将提供新的关于特定氧脂素对肌肉代谢和线粒体功能的影响的信息。最后，在Aim 3、我们将测试是否在肌肉特异性Alox 15 KO小鼠中体内抑制氧脂素产生或降低水平在Gpx 4表达水平升高的小鼠中，脂质过氧化氢（LOOH）的表达可以防止年龄相关的衰老小鼠体内肌肉萎缩。我们预测oxPL/oxlipins的生成减少，脂质过氧化氢（LOOH）的解毒将改变目标1中概述的萎缩目标，衰老小鼠的萎缩和虚弱。总的来说，这些实验将是第一次调查氧化脂质的作用，在肌肉减少症和他们的潜力作为目标干预肌肉损失和无力。