Regulation of Mitochondrial Gene Expression and Function by GDF11 Signaling

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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.