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

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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.