Metabolic Reprogramming Laboratory, Metabolic Research Unit, School of Medicine and Centre for Molecular and Medical Research, Deakin University
A lack of physical activity is contributing to a scourge of chronic diseases including obesity, type 2 diabetes, cardiovascular disease and cancer through a loss of functional capacity and impaired muscle metabolism. Understanding the molecular responses mediating skeletal muscle adaptations to exercise presents an opportunity to identify targets to enhance functional capacity and muscle metabolism. Given that transient alterations in skeletal muscle gene expression are thought to mediate many of the beneficial adaptive effects of exercise, our efforts in understanding these responses has been focused on epigenetics and epigenetic regulators. Our initial studies in humans showed that a signaling pathway involving histone 3 acetylation, the MEF2 transcription factor and disruption of the class IIa histone deacetylase corepressor complex is associated with exercise-induced gene expression. These findings suggested that the class IIa HDACs could be a viable target to therapeutically induce exercise adaptations. Studies in mice confirmed that genetic disruption of the class IIa HDACs corepressor complex invoked adaptive responses similar to exercise, including increased metabolic gene expression, increased oxidative capacity and lipid oxidation. Screening of compounds with similar phenotypic effects revealed Scriptaid as a compound that disrupts the class IIa HDAC corepressor complex. Chronic Scriptaid administration to mice increased exercise capacity, enhanced whole body energy expenditure and lipid oxidation and reduced blood glucose and lipids. These studies highlight the value in understanding the molecular responses underpinning human physiology and show that pharmacological targeting of the class II HDAC corepressor complex could be a strategy to combat chronic diseases associated with physical inactivity.