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 与年龄相关的肌肉萎缩或肌肉减少症会影响老年人的15％，生活质量降低并增加 发病率和死亡率。在衰老期间，骨骼肌会经历结构和功能改变 多个失调的途径。由于这种多因素的病因，释放因果分子途径 为了确定预防治疗靶标，延迟或逆转肌肉减少症已被证明具有挑战性。我们的目标 是为了阐明肌肉减少症的新因果机制，并利用这些知识来改善老化的肌肉功能。 我们的初步数据显示，老年肌肉中特定的脂质前​​列腺素代谢产物的降低。我们 最近发现，这种降低是由15-羟基丙烷蛋白脱氢酶的分解代谢引起的（15-- PGD​​H），前列腺素降解酶，在老年小鼠和人类肌肉中明显增加。 为了确定15-PGDH在肌肉减少症中的作用，我们过表达了年轻肌肉中的酶，观察到a 预测PGE2和PGD2水平的降低，伴随着意外明显的下降 在肌肉质量和功能中，模仿了肌肉减少症的关键特征。发现15-PGDH上调 老年肌肉中前列腺素水平的同时降低构成了拟议研究的基础 以前无法实现有针对性的分子和功能研究。我们假设在衰老期间 衰老和炎症细胞积累在肌肉微环境中，并表达15-PGDH，这 降解PGE2和PGD2，并导致肌肉浪费。我们进一步假设抑制15-PGDH 老化的肌肉将增加PGE2和PGD2脂质代谢产物，并增加肌肉质量和力量。在 拟议的研究我们旨在（i）阐明脂质前列腺素PGE2和PGD2代谢物在 骨骼肌稳态，（ii）确定老年人的细胞来源15-PGDH和前列腺素失调 肌肉和（iii）通过抑制分解代谢酶15-恢复肌肉功能和老化肌肉的质量 PGD​​H。这项工作将受益于我们以前开发的用于量化前列腺素水平的技术： 使用非侵入性方法，基于质谱的脂质分析和肌肉力评估。 此外，我们将利用我们最近为骨骼肌肉进行优化的单细胞技术 组织，多路复用组织成像（也称为法典，通过索引共检测），可解析高达60 同时在单组织切片中标记。法典将确定是否衰老细胞 包括15-PGDH的细胞来源，并分辨出老化的各种细胞类型之间的空间关系 肌肉。这些研究将共同​​提供有关一种新型失调途径脂质前列腺素的见解 衰老肌肉的信号传导，并确定是否抑制由15-PGDH介导的PGE2和PGD2分解代谢， 老化的肌肉质量和功能。这项研究将确定脂质信号传导机制的出现 衰老并为肌肉减少症提供治疗策略。