Regulation of Mitochondrial Gene Expression and Function by GDF11 Signaling

项目摘要。骨骼肌越来越多地被认为是一种内分泌组织， 通过分泌肌源性生长因子和细胞因子调节生理稳态， 肌因子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缺乏的限制。 老鼠的寿命很长。在过去的几十年里，寿命较短的生物，如果蝇， 被证明有助于解剖调节衰老的内分泌信号通路。我们发现 肌细胞因子Myoglianin（人GDF 11的同系物）调节果蝇的组织衰老和寿命。GDF11 据报道，它可以延缓小鼠的衰老，但所涉及的分子和细胞机制在很大程度上是 未知为了研究它的作用，我的小组已经分析了由 Myoglianin/GDF 11样信号在肌肉中的作用，并发现它调节许多相关基因的表达， 线粒体功能和代谢的重要性。之后，我们计算分析了启动子区域， 的肌球蛋白调节基因和鉴定的转录因子结合基序，是丰富的。与 在随后的功能研究中，我们已经定义了一组转录因子，它们作用于 Myoglianin/GDF 11样信号传导和调节线粒体基因表达。根据这些 根据初步数据，我的小组现在提出确定：1）Myoglianin调节的机制 促进线粒体基因表达的下游转录因子; 2） 线粒体功能的肌球蛋白在衰老过程中;和3）线粒体功能的内分泌调节， 非肌肉组织如大脑对肌肉来源的肌球蛋白的反应。圆满完成 这项研究将为Myoglianin/GDF 11样蛋白的作用机制提供新的见解。 信号传导延缓衰老及其在延长人类健康寿命中的可能作用。

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.