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

• 批准号: 10634523
• 负责人: Helen M Blau
• 金额: $ 40.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634523
• 关键词: Ablation; 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 Inhibition; Prostaglandin Receptor; Prostaglandins; Protein Analysis; Public Health; Quality of life; Regulation; Research; Resolution; Role; Second Messenger Systems; Signal Induction; Signal Transduction; Skeletal Muscle; Source; Structure; Techniques; Testing; Therapeutic; Time; Tissue imaging; Tissues; Transgenic Mice; Up-Regulation; Visualization; Work; age related; aged; 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

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.

项目摘要 肥胖相关的肌肉萎缩或肌肉减少症影响15%的老年人，降低生活质量，增加 发病率和死亡率。随着年龄的增长，骨骼肌的结构和功能也随之发生变化 多种失调的途径。由于这种多因素病因，解开因果分子途径 以确定治疗靶点来预防、延迟或逆转肌肉减少症已被证明具有挑战性。我们的目标 目的是阐明肌肉减少症的新的致病机制，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，在老年肌肉中特定的脂质前列腺素代谢物减少。我们 最近发现，这种减少是由15-羟基前列腺素脱氢酶（15- PGDH），前列腺素降解酶，在老年小鼠和人体肌肉中显著增加。 为了确定15-PGDH在肌肉减少症中的作用，我们在年轻的肌肉中过表达该酶，观察到15-PGDH在肌肉减少症中的作用。 预测PGE 2和PGD 2水平降低，伴随着意外的显著降低 在肌肉质量和功能方面，模仿肌肉减少症的关键特征。发现15-PGDH上调 以及伴随的老年肌肉中前列腺素水平的降低形成了所提出的研究的基础， 使以前无法进行的靶向分子和功能研究成为可能。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累，并表达15-PGDH， 降低PGE 2和PGD 2，导致肌肉萎缩。我们进一步假设，抑制15-PGDH， 老化的肌肉将增加PGE 2和PGD 2脂质代谢物，并增加肌肉质量和力量。在 我们提议的研究旨在（i）阐明脂质前列腺素PGE 2和PGD 2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，和（iii）通过抑制分解代谢酶15- 18，恢复肌肉功能和老化肌肉的质量。 PGDH。这项工作将受益于我们以前开发的量化前列腺素水平的技术： 基于质谱的脂质分析和使用非侵入性方法随时间推移的肌肉力量评估。 此外，我们将利用单细胞技术，我们最近优化的骨骼肌研究 组织，多路组织成像（也称为CODEX，通过indEXing进行CO检测），分辨率高达60 标记物同时在单个组织切片中。CODEX将能够确定衰老细胞是否 包括15-PGDH的细胞来源和老年不同细胞类型之间空间关系的解决 肌肉.总之，这些研究将提供一个新的失调途径，脂质前列腺素的见解 信号，并确定是否抑制PGE 2和PGD 2催化剂介导的15-PGDH，aug- 使肌肉质量和功能老化。这项研究将确定脂质信号传导机制， 衰老和告知治疗策略的肌肉减少症。