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Epigenetic and Transcriptional Control of Skeletal Muscle Regeneration and Metabolism
Prof Thomas Braun, Director, Max Planck Institute for Heart and Lung Research; Professor of Internal Medicine, University of Giessen
日期 : 2018年 2月 2日 (星期五)
時間 : 下午4時至5時30分
地點 : 香港科技大學 夏利萊博士及夫人演講廳 (LT-C)
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Abstract

Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since the expression of several muscle-specific microRNA (miRNA) genes correlates with the increased mitochondrial activity during muscle stem cell differentiation, the speaker examined their potential roles in metabolic maturation of skeletal muscles in mice. He found that miRs downregulate Myocyte-specific enhancer factor 2A (Mef2A) in differentiated myocytes thereby suppressing the delta-like homolog 1 gene and type III iodothyronine deiodinase gene (Dlk1-Dio3) cluster, which encodes multiple miRNAs inhibiting expression of mitochondrial genes. Loss of Mef2A suppression in skeletal muscles or increased Mef2A expression causes continuous high-level expression of the Dlk1-Dio3 gene cluster compromising mitochondrial function. Failure to terminate the stem cell-like metabolic program characterized by high-level Dlk1-Dio3 gene cluster expression initiates profound changes in muscle physiology, essentially abrogating endurance running. The results suggest a major role of miRNAs in metabolic maturation of skeletal muscles but exclude major functions in muscle development and maintenance.

Furthermore, he investigated the molecular circuits controlling survival of muscle stem cells in damaged muscles, which are not well understood. He found that muscle stem cells isolated from dystrophic muscle maintain an increased propensity for programmed cell death even after several divisions in culture arguing for an epigenetic control mechanism that directs expression of molecules involved in programmed cell death. To identify epigenetic processes that might prevent untimely activation of programmed cells death in muscle stem cells, he conducted a non-biased high-throughput lentiviral RNA interference (RNAi) screen for all known chromatin modifiers and identified a chromatin remodeling complex that prevents increased activation of programmed apoptosis, also known as necroptosis. Genetic inactivation of the chromatin modifier complex in muscle stem cells in vivo resulted in strong activation of Receptor-interacting serine/threonine-protein kinase 3 (Ripk3) expression, an essential component of the necroptosis pathway. Enhanced necroptosis prevented expansion of muscle stem cells after injury and abrogated efficient muscle regeneration. Interestingly, epigenetic repression of Ripk3 expression was reduced in dystrophic muscle, which might explain the increased number of muscle stem cells undergoing programmed cell death in disease conditions.
 

 

 

About the speaker

Prof Thomas Braun received his medical degree from the University of Hamburg in 1987. He then started his research career as a Postdoctoral Researcher at the University of Hamburg and moved to MIT in 1990. He became the Assistant Professor of Molecular and Cellular Biology of the Technical University of Braunschweig in 1992. He joined the University of Würzburg as Professor and Director of Institute for Physiological Chemistry in 1997. He is currently the Professor of Internal Medicine at University of Giessen and Director of Max Planck Institute for Heart and Lung Research.

Prof Braun is a renowned developmental and stem cell biologist in Europe. His group routinely publishes research papers in leading biomedical journals. His publications in 2017 include "Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages", "Disruption of Spatiotemporal Hypoxic Signaling Causes Congenital Heart Disease in Mice" and "Sirt7 Promotes Adipogenesis in the Mouse by Inhibiting Autocatalytic Activation of Sirt1".

Prof Braun’s research is well recognized through numerous awards. He was the elected members of Academia Europea (2013), Max-Planck-Society (2004) and the Leopoldina, the German Academy of Sciences (2001).
 

For attendees’ attention

 

  The lecture is free and open to all. Seating is on a first come, first served basis.

 

 

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