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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.

摘要。肌肉减少症，肌肉质量和功能的损失随着年龄的增长，是一个普遍的问题