Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging

调节类二十烷酸信号脂质以改善骨骼肌功能并延长衰老过程中的健康寿命

基本信息

批准号：
10402400
负责人：
Helen M Blau
金额：
$ 40.2万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402400
关键词：
Affect Age Aging Antibodies Area Autophagocytosis Binding Catabolism Catalysis Cell Cycle Arrest Cells Cessation of life Characteristics Data Detection Dinoprostone Disease Eicosanoids Elderly Enzymes Etiology Evaluation G-Protein-Coupled Receptors Goals Health Expenditures Histology Homeostasis Human Individual Inflammatory Injury Knowledge Lead Lipids Mediating Methods Mitochondria Molecular Molecular Target Morbidity - disease rate Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Outcome Oxidoreductase Pathway interactions Persons Phenocopy Play Process Prostaglandin D2 Prostaglandin Receptor Prostaglandins Protein Analysis Public Health Quality of life Regulation Research Resolution Role Second Messenger Systems Signal Transduction Skeletal Muscle Source Structure Techniques Testing Therapeutic Time Tissue imaging Tissues Transgenic Mice Up-Regulation Work age related aged base cell type experimental study healthspan improved indexing inhibitor insight knock-down loss of function mortality mouse model multiplexed imaging muscle aging muscle form muscle regeneration muscle strength novel novel marker overexpression physically handicapped premature prevent protein degradation receptor sarcopenia senescence single cell technology skeletal muscle wasting small molecule inhibitor spatial relationship therapeutic target time use transcriptomics

项目摘要

PROJECT SUMMARY Age-related muscle atrophy, or sarcopenia, affects 15% of the elderly, diminishing quality of life and increasing morbidity and mortality. During aging, skeletal muscles undergo structural and functional alterations as a result of multiple dysregulated pathways. Due to this multifactorial etiology, untangling the causal molecular pathways in order to identify therapeutic targets to prevent, delay or reverse sarcopenia has proven challenging. Our goal is to elucidate novel causal mechanisms of sarcopenia and use this knowledge to improve aged muscle function. Our preliminary data has revealed a reduction in specific lipid prostaglandin metabolites in aged muscles. We recently discovered that this reduction resulted from catabolism by 15-hydroxyprostaglandin dehydrogenase (15- PGDH), the prostaglandin degrading enzyme, which is markedly increased in aged mouse and human muscles. To determine the role of 15-PGDH in sarcopenia, we overexpressed the enzyme in young muscles, observed a predicted reduction in PGE2 and PGD2 levels, which was accompanied by an unexpectedly marked decrease in muscle mass and function, mimicking key features of sarcopenia. The discovery of 15-PGDH upregulation and concomitant decrease in prostaglandin levels in aged muscle forms the basis for the proposed research and enables targeted molecular and functional studies previously not possible. We hypothesize that during aging, senescent and inflammatory cells accumulate in the muscle microenvironment and express 15-PGDH, which degrades PGE2 and PGD2, and causes muscle wasting. We further hypothesize that inhibition of 15-PGDH in aged muscles will increase PGE2 and PGD2 lipid metabolites and augment muscle mass and strength. In the proposed research we aim to (i) elucidate the role of the lipid prostaglandin PGE2 and PGD2 metabolites in skeletal muscle homeostasis, (ii) identify the cell source of 15-PGDH and prostaglandin dysregulation in aged muscle, and (iii) restore muscle function and mass of aged muscles by inhibiting the catabolic enzyme, 15- PGDH. This work will benefit from techniques we have previously developed to quantify prostaglandin levels: mass-spectrometric-based lipid profiling and muscle force assessments over time using non-invasive methods. Further, we will capitalize on a single-cell technology we recently optimized for the study of skeletal muscle tissue, multiplexed tissue imaging (also known as CODEX, CO-Detection by indEXing), that resolves up to 60 markers simultaneously in single tissue sections. CODEX will enable a determination of whether senescent cells comprise a cell source of 15-PGDH and resolution of spatial relationships among the diverse cell types in aged muscles. Together, these studies will provide insights into a novel dysregulated pathway, lipid prostaglandin signaling in aged muscles, and determine if inhibiting PGE2 and PGD2 catabolism mediated by 15-PGDH, aug- ments aged muscle mass and function. This research will identify lipid signaling mechanisms that go awry in aging and inform therapeutic strategies for sarcopenia.

项目概要 15% 的老年人患有与年龄相关的肌肉萎缩或肌肉减少症，这会降低生活质量并增加发病率和死亡率。在衰老过程中，骨骼肌会发生结构和功能的变化多种失调途径。由于这种多因素病因学，解开因果分子途径事实证明，确定预防、延迟或逆转肌肉减少症的治疗靶点具有挑战性。我们的目标目的是阐明肌肉减少症的新因果机制，并利用这些知识来改善老年肌肉功能。我们的初步数据显示，衰老肌肉中特定的脂质前列腺素代谢物有所减少。我们最近发现这种减少是由于 15-羟基前列腺素脱氢酶 (15- PGDH），前列腺素降解酶，在老年小鼠和人类肌肉中显着增加。为了确定 15-PGDH 在肌肉减少症中的作用，我们在年轻肌肉中过度表达该酶，观察到预测 PGE2 和 PGD2 水平下降，并伴随着意想不到的显着下降肌肉质量和功能，模仿肌肉减少症的关键特征。 15-PGDH上调的发现衰老肌肉中前列腺素水平的随之下降构成了拟议研究的基础实现以前不可能进行的靶向分子和功能研究。我们假设在衰老过程中，衰老和炎症细胞在肌肉微环境中积聚并表达 15-PGDH，降解 PGE2 和 PGD2，并导致肌肉萎缩。我们进一步假设 15-PGDH 的抑制老化的肌肉会增加 PGE2 和 PGD2 脂质代谢并增加肌肉质量和力量。在我们提出的研究旨在 (i) 阐明脂质前列腺素 PGE2 和 PGD2 代谢物在骨骼肌稳态，(ii) 确定老年人 15-PGDH 和前列腺素失调的细胞来源肌肉，以及（iii）通过抑制分解代谢酶来恢复肌肉功能和老化肌肉的质量，15- PGDH。这项工作将受益于我们之前开发的量化前列腺素水平的技术：使用非侵入性方法随时间进行基于质谱的脂质分析和肌肉力量评估。此外，我们将利用我们最近为骨骼肌研究而优化的单细胞技术组织，多重组织成像（也称为 CODEX，通过 indEXing 进行的联合检测），可解析高达 60 在单个组织切片中同时标记。 CODEX 将能够确定衰老细胞是否包括 15-PGDH 的细胞来源以及老年人不同细胞类型之间空间关系的分辨率肌肉。总之，这些研究将提供对一种新的失调途径——脂质前列腺素——的见解。衰老肌肉中的信号传导，并确定是否抑制 15-PGDH 介导的 PGE2 和 PGD2 分解代谢，aug- 老化的肌肉质量和功能。这项研究将确定在以下情况下出错的脂质信号传导机制：衰老并为肌肉减少症的治疗策略提供信息。