LOOH-induced muscle atrophy with age
随着年龄的增长,LOOH 引起的肌肉萎缩
基本信息
- 批准号:10588970
- 负责人:
- 金额:$ 7.31万
- 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:2022-02-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:ATG3 geneAcyltransferaseAffectAgeAgingAldehydesAtrophicAutophagocytosisAutophagosomeCaliberCarboxy-LyasesCardiovascular DiseasesCell DeathCell SizeClinicalCollectionDataEnzymesHydroxyl RadicalIn VitroKnowledgeLeadLecithinLipid PeroxidesLipidsLysophosphatidylcholinesLysosomesMaintenanceMedicalMembraneMetabolic DiseasesMitochondriaModelingMolecularMusMuscle CellsMuscle FibersMuscle WeaknessMuscle functionMuscular AtrophyNatureOxidative StressPathway interactionsPharmacologyPhosphatidylethanolaminePhosphatidylserinesPhospholipidsPlayPolyunsaturated Fatty AcidsPopulationProductionProtein BiosynthesisProteolysisQuality of lifeReactionReactive Oxygen SpeciesRoleSignal TransductionSkeletal MuscleSourceStressTestingTherapeuticWateraging populationbasecell injurycell typediet and exerciseexperimental studyglutathione peroxidasehealthy agingin vivoinhibition of autophagymuscle agingmuscle formmuscle strengthnovel strategiesoverexpressionpi bondpreventprotein degradationsarcopeniasedentaryskeletal muscle wasting
项目摘要
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
骨骼肌质量的维持对于健康老龄化至关重要,并在生活质量中起着重要作用。
骨骼肌萎缩症(肌肉减少症)不仅降低了活动能力,
代谢和心血管疾病虽然骨骼肌萎缩具有广泛的临床影响,
在日益久坐和老龄化的人群中,肌肉质量损失的药物治疗不
存在.活性氧(ROS)可能通过加速蛋白质降解和抑制蛋白质降解而导致肌肉萎缩。
蛋白质合成。然而,ROS是指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下游后果是造成细胞内
肌肉质量和功能随年龄或废用而发生。在本申请中,我们将测试我们的假设,
脂质ROS(LOOH)通过加速自噬/溶酶体依赖蛋白促进肌肉萎缩
降解1)细胞LOOH被磷脂过氧化氢酶(GPx 4)中和,防止其
积累和降解形成反应性脂质醛。我们将决定是否中和
通过N-乙酰肌肽处理(脂质醛清除剂)的LOOH将抑制年龄和/或废用诱导的
骨骼肌萎缩2)多不饱和脂肪酸(PUFA)掺入的抑制
溶血磷脂酰胆碱酰基转移酶-3(LPCAT 3)抑制防止LOOH诱导的细胞死亡。我们将
研究LPCAT 3缺失是否可以保护小鼠免受肌肉萎缩,并进行亚细胞通量组学
以检查氧化应激期间LPCAT 3产物的细胞内命运。3)GPx 4缺失增加蛋白质
通过加速溶酶体降解来降解。我们将测试我们的假设,LOOH增压
自噬机制通过其与LC 3的脂化来实现。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Micah J Drummond其他文献
Micah J Drummond的其他文献
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{{ truncateString('Micah J Drummond', 18)}}的其他基金
MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
- 批准号:
10817445 - 财政年份:2022
- 资助金额:
$ 7.31万 - 项目类别:
Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
- 批准号:
10622569 - 财政年份:2022
- 资助金额:
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Regulation of macrophage metabolism in aged muscle during recovery
衰老肌肉恢复过程中巨噬细胞代谢的调节
- 批准号:
10460028 - 财政年份:2022
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$ 7.31万 - 项目类别:
MicroRNA regulation of chronic inflammation during aging
MicroRNA对衰老过程中慢性炎症的调节
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10531053 - 财政年份:2022
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$ 7.31万 - 项目类别:
Targeting macrophage polarization to optimize muscle regrowth from disuse atrophy
靶向巨噬细胞极化以优化废用性萎缩的肌肉再生
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10197500 - 财政年份:2019
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