Regulation of Mitochondrial Gene Expression and Function by GDF11 Signaling

项目摘要。骨骼肌越来越被认为是一种内分泌组织，具有以下能力： 通过分泌肌肉源性生长因子和细胞因子来调节生理稳态 肌动蛋白。尽管肌因子可能调节哺乳动物的衰老，但这些研究受到相对 老鼠的寿命长。在过去的几十年里，寿命较短的生物，如果蝇，已经 已被证明有助于剖析调节衰老的内分泌信号通路。我们发现 肌因子肌细胞蛋白（人类 GDF11 的同源物）调节果蝇的组织衰老和寿命。 GDF11 据报道可以延缓小鼠衰老，但所涉及的分子和细胞机制很大程度上是 未知。为了研究其作用，我的小组分析了由 肌肉中的肌胶质蛋白/GDF11 样信号传导，发现它调节许多相关基因的表达 线粒体功能和代谢。之后，我们对启动子区域进行了计算分析 肌胶质蛋白调节基因并鉴定出富集的转录因子结合基序。与 随后的功能研究，我们定义了一组作用于下游的转录因子 肌胶质蛋白/GDF11 样信号传导并调节线粒体基因表达。在这些基础上 初步数据，我的小组现在建议确定：1）肌胶质蛋白调节的机制 促进线粒体基因表达的下游转录因子； 2）监管 衰老过程中肌胶质蛋白的线粒体功能； 3）线粒体功能的内分泌调节 非肌肉组织（例如大脑）对肌肉来源的肌胶质蛋白做出反应。顺利完成 这项研究将为 Myoglianin/GDF11-like 的机制提供基本的新见解 信号传导可以延缓衰老及其在延长人类健康寿命方面的可能作用。

PROJECT SUMMARY. Skeletal muscle is increasingly recognized as an endocrine tissue with the capacity to regulate physiological homeostasis via the secretion of muscle-derived growth factors and cytokines known as myokines. Although myokines may regulate aging in mammals, these studies are hampered by the relatively long lifespan of mice. Over the past decades, shorter-lived organisms, such as the fruit fly Drosophila, have proven instrumental in dissecting the endocrine signaling pathways that regulate aging. We have found that the myokine Myoglianin (the homolog of human GDF11) regulates tissue aging and lifespan in Drosophila. GDF11 has been reported to delay aging in mice but the molecular and cellular mechanisms involved are largely unknown. To investigate its action, my group has profiled the gene expression changes induced by Myoglianin/GDF11-like signaling in muscle and found that it regulates the expression of many genes involved in mitochondrial function and metabolism. Afterwards, we have computationally analyzed the promoter regions of Myoglianin-regulated genes and identified transcription factor binding motifs that are enriched. With subsequent functional studies, we have defined a set of transcription factors that act downstream of Myoglianin/GDF11-like signaling and regulate mitochondrial gene expression. On the basis of these preliminary data, my group now proposes to determine: 1) the mechanisms by which Myoglianin regulates downstream transcription factors that promote mitochondrial gene expression; 2) the regulation of mitochondrial function by Myoglianin during aging; and 3) the endocrine modulation of mitochondrial function in non-muscle tissues such as the brain in response to muscle-derived Myoglianin. The successful completion of this research will provide fundamental new insight into the mechanisms by which Myoglianin/GDF11-like signaling delays aging and its possible roles in extending healthy lifespan in humans.