Epigenetic regulation of the angiogenic capacity in skeletal muscle and adipose tissues: Role of histone modifiers during endurance exercise

骨骼肌和脂肪组织血管生成能力的表观遗传调控：组蛋白修饰剂在耐力运动中的作用

• 批准号: RGPIN-2020-07142
• 负责人: Roudier, Emilie
• 金额: $ 2.04万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757809
• 关键词: Epigenetic; regulation; angiogenic; capacity; skeletal

When performing an endurance exercise, such as a long run, our skeletal muscles contract and need energy. The fat tissue, also called adipose tissue, stores fat. During exercise, this fat is mobilized, released in the blood circulation and delivered to the muscle where it serves as a source of energy. This fat mobilization would not be optimal without a proper network of small blood vessels, the capillaries. In both tissues, this network of capillaries expands in response to endurance training by a process called angiogenesis, the formation of new capillaries from existing blood vessels. This process is controlled by changes in the expression of specific genes, the angiogenesis-related genes. When one endurance exercise is performed, there is a massive change in gene expression in skeletal muscle and adipose tissues. Indeed, more than 3,200 genes respond to the bout of exercise. This change in gene expression persists only for few hours. When bouts of exercise are repeated regularly during training, the cumulative effect of these cyclic changes in gene expression support adaptation, including angiogenesis. After weeks of training, the skeletal muscle and adipose tissues have adapted. And even if training continues, the capillary network cannot expand further. It remains unclear how angiogenesis stops. A decrease in the sensitivity of genes, including angiogenesis-related genes, was reported after 6 to 8 weeks of training. Only 400 genes (out of 3,200) remain able to respond to the bout of exercise. This suggests that many genes may be silenced. Since the decay in the sensitivity of genes to the bout of exercise is remarkable, we propose that an active process called histone marking may silence gene expression. Histone proteins act to package DNA. Histone marking is an epigenetic process that changes DNA accessibility and modulates gene expression. Histone modifiers are the enzymes that catalyze these marks. Some histone marks activate gene expression, others silence it. Silencing histone marks had not been studied in the context of training, until my newly established research team observed that endurance training increases the muscle abundance of silencing histone marks and the expression of two histone modifiers: the E3 ubiquitin ligase MDM2 and the histone methyltransferase EZH2. In contexts other than physical training, other researchers have recently shown that MDM2 and EZH2 interact and establish silencing marks on histones. As a research associate, I have previously shown that MDM2 senses exercise and regulates angiogenesis-related genes. Based on these observations, my research program aims to study if the apposition of silencing marks by histone modifiers during training support the remarkable decay in the sensitivity of genes to the bout of exercise in the skeletal muscle and adipose tissues. To initiate this program, we will first study the role of the histone modifiers, MDM2 and EZH2, in silencing angiogenesis-related genes.

当进行耐力运动时，比如长跑，我们的骨骼肌会收缩，需要能量。脂肪组织，也称为脂肪组织，储存脂肪。在运动过程中，这种脂肪被动员，在血液循环中释放并输送到肌肉，在那里它作为能量来源。如果没有适当的小血管网络，即毛细血管，这种脂肪动员就不会是最佳的。在这两种组织中，这种毛细血管网络都会通过一种称为血管生成的过程（从现有血管形成新毛细血管）来响应耐力训练而扩张。这一过程是由特定基因（血管生成相关基因）表达的变化控制的。当进行一次耐力运动时，骨骼肌和脂肪组织中的基因表达会发生巨大变化。事实上，超过3，200个基因对运动做出反应。这种基因表达的变化只持续几个小时。当训练期间定期重复运动时，这些基因表达周期性变化的累积效应支持适应，包括血管生成。经过几周的训练，骨骼肌和脂肪组织已经适应了。即使训练继续下去，毛细血管网络也不能进一步扩展。目前尚不清楚血管生成如何停止。据报道，经过6至8周的训练，包括血管生成相关基因在内的基因敏感性降低。只有400个基因（在3,200个基因中）仍然能够对运动做出反应。这表明许多基因可能是沉默的。由于基因对运动敏感性的衰减是显着的，我们提出一种称为组蛋白标记的活跃过程可能会沉默基因表达。组蛋白的作用是包装DNA。组蛋白标记是改变DNA可及性和调节基因表达的表观遗传过程。组蛋白修饰剂是催化这些标记的酶。一些组蛋白标记激活基因表达，另一些则沉默。沉默组蛋白标记没有在训练的背景下进行过研究，直到我新成立的研究团队观察到耐力训练增加了沉默组蛋白标记的肌肉丰度和两种组蛋白修饰剂的表达：E3泛素连接酶MDM 2和组蛋白甲基转移酶EZH 2。在体能训练以外的环境中，其他研究人员最近表明，MDM 2和EZH 2相互作用，并在组蛋白上建立沉默标记。作为一名研究助理，我之前已经证明了MDM 2可以感知运动并调节血管生成相关基因。 基于这些观察，我的研究计划旨在研究在训练过程中组蛋白修饰剂沉默标记的并置是否支持骨骼肌和脂肪组织中基因对运动的敏感性显着衰减。为了启动这个项目，我们将首先研究组蛋白修饰剂MDM 2和EZH 2在沉默血管生成相关基因中的作用。