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:
- 金额:$ 56.33万
- 依托单位:
- 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:
- 关键词:AffectAgeAgingArachidonate 15-LipoxygenaseArachidonic AcidsAtrophicAutophagocytosisCell DeathCellsDataDegradation PathwayDenervationDevelopmentDiameterDrug Metabolic DetoxicationEffectivenessElderlyEnzymesGenerationsGoalsIn VitroIndividualInterventionKnockout MiceLinkLipid PeroxidesMeasuresMediatingMediatorMembraneMitochondriaModelingMusMuscleMuscle CellsMuscle FibersMuscle MitochondriaMuscle WeaknessMuscle functionMuscular AtrophyPathway interactionsPatternPhospholipase A2PhospholipidsPopulationProductionPublic HealthPublishingQuality of lifeRiskRoleTestingWild Type MouseWorkage relatedage-related muscle lossdesigneffective interventionexperimental studyfallsfrailtyhealthspanimprovedin vivoinhibitorinsightintervention effectlipid mediatormuscle formmuscle metabolismnerve supplynoveloxidationoxidative damageoxidized lipidpharmacologicpreventprotective effectprotein degradationproteostasisresponsesarcopeniasuccessful interventiontherapeutic 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。
项目成果
期刊论文数量(0)
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HOLLY VAN REMMEN其他文献
HOLLY VAN REMMEN的其他文献
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{{ truncateString('HOLLY VAN REMMEN', 18)}}的其他基金
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
- 批准号:
10608413 - 财政年份:2022
- 资助金额:
$ 56.33万 - 项目类别:
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$ 56.33万 - 项目类别:
Testing OKN-007 as a potential intervention for ALS
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10513312 - 财政年份:2021
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Activation of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) as a Therapeutic Intervention for Sarcopenia
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- 批准号:
10166596 - 财政年份:2019
- 资助金额:
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Activation of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) as a Therapeutic Intervention for Sarcopenia
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