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

项目总结 与年龄相关的肌肉萎缩，或骨质疏松症，影响15%的老年人，降低生活质量，增加 发病率和死亡率。在衰老过程中，骨骼肌经历了结构和功能的变化 多条调节失调的通路。由于这种多因素的病因学，解开了病因的分子途径 为了确定预防、延缓或逆转骨质疏松症的治疗靶点，已证明具有挑战性。我们的目标 目的是阐明骨质疏松症的新的致病机制，并利用这一知识来改善老年肌肉功能。 我们的初步数据显示，老年肌肉中特定的脂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-羟基前列腺素脱氢酶)分解代谢引起的。 前列腺素降解酶)，这种酶在衰老的小鼠和人的肌肉中显著增加。 为了确定15-前列腺素脱氢酶在石棺减少症中的作用，我们在年轻肌肉中过度表达了这种酶，观察到 预测PGE2和PGD2水平下降，同时伴随着出人意料的显著下降 在肌肉质量和功能上，模仿石棺减少症的主要特征。15-前列腺素脱氢酶上调的发现 而伴随而来的衰老肌肉中前列腺素水平的下降构成了拟议的研究和 使以前不可能进行的有针对性的分子和功能研究成为可能。我们假设在衰老过程中， 衰老和炎性细胞聚集在肌肉微环境中，并表达15-PGDH，这是 降解PGE2和PGD2，并导致肌肉萎缩。我们进一步假设，15-前列腺素脱氢酶抑制血管紧张素转换酶 衰老的肌肉会增加PGE2和PGD2的脂肪代谢产物，增加肌肉质量和力量。在 我们的目标是：(I)阐明脂类前列腺素PGE2和前列腺素D2代谢物在 骨骼肌内稳态，(II)老年人15-前列腺素脱氢酶和前列腺素失衡的细胞来源 肌肉，以及(Iii)通过抑制分解代谢酶来恢复衰老肌肉的肌肉功能和质量，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推移基于质谱学的脂谱和肌肉力量评估。 此外，我们将利用我们最近优化的单细胞技术来研究骨骼肌 组织，多路复用组织成像(也称为Codex，通过索引进行联合检测)，分辨率高达60 标记物同时出现在单个组织切片上。食品法典将能够确定衰老细胞是否 包括15-前列腺素脱氢酶的细胞来源和老年人不同细胞类型之间的空间关系的解析 肌肉。总之，这些研究将为一种新的失调途径--脂类前列腺素提供洞察力 在衰老肌肉中的信号，并确定是否抑制PGE2和PGD2的分解代谢介导的15-PGDH，8月- 老化的肌肉质量和功能。这项研究将确定脂类信号转导机制的错误 老化并为石棺减少症的治疗策略提供信息。

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.