Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

Class IIa HDACs link skeletal muscle metabolic remodelling with muscle cell survival in type 2 diabetes  (#159)

Sean L McGee 1
  1. Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, VIC, Australia

In type 2 diabetes, transcriptional and metabolic remodeling in skeletal muscle is thought to contribute to impaired oxidative metabolism, lipid accumulation and insulin resistance. However, the molecular mechanisms contributing to this response are also unknown. Here we present evidence to suggest that increased class IIa histone deactylases (HDACs) in skeletal muscle contributes to the transcriptional and metabolic remodelling seen in type 2 diabetes. Over-expression of the class IIa HDACs phenocopies muscle in the diabetic state, while genetic inactivation of class IIa HDAC activity prevents muscle transcriptional and metabolic remodeling in diabetic mice. Comparative genomic approaches reveal that the increase in class II HDACs seen in diabetes occurs to prevent skeletal muscle apoptosis by metabolic insults. However, regulation of metabolism and protection from apoptosis by the class IIa HDACs occurs via distinct enzymatic functions. We are currently designing novel small molecules that exploit this divergence in class IIa HDAC function to enhance metabolism, without altering muscle cell sensitivity to apoptosis, as a potential therapeutic strategy to normalize muscle metabolism in type 2 diabetes.