Histone deacetylase inhibition replicates aspects of the adaptive response to exercise and improves muscle metabolism and cardiac function in obesity.. Mus musculus

Drugs used to treat obesity and type 2 diabetes have limited efficacy in directly normalising muscle metabolism. The discovery of molecules mediating exercise adaptations, and drugs that modulate their activity, is a potential strategy to address this therapeutic gap. Here we show that genetic impairment of HDAC4 and 5 in mice regulated a subset of exercise responsive genes involved in metabolism and increased cell autonomous energy expenditure. Screening of HDAC inhibitors identified Scriptaid as a compound that also replicated aspects of the exercise adaptive response in vitro and in vivo. Treatment of obese mice with Scriptaid increased exercise performance, restored muscle insulin sensitivity and reduced muscle lipids. Scriptaid also increased oxygen consumption and normalised cardiac structure and function in obese mice. These data show that HDAC inhibition replicates aspects of the exercise adaptive response and that pharmacological HDAC inhibition could deliver more efficacious treatment to combat the metabolic diseases. Overall design: Four-condition experiment, Empty, HDACs, Vehicle and Script-HDACs with five biological replicates for each condition. One replicate per array.