The class IIa histone deacetylases (HDACs) act as transcriptional repressors by 
altering chromatin structure through histone deacetylation. This family of 
enzymes regulates muscle development and phenotype, through regulation of 
muscle-specific genes including myogenin and MyoD (MYOD1). More recently, class 
IIa HDACs have been implicated in regulation of genes involved in glucose 
metabolism. However, the effects of HDAC5 on glucose metabolism and insulin 
action have not been directly assessed. Knockdown of HDAC5 in human primary 
muscle cells increased glucose uptake and was associated with increased GLUT4 
(SLC2A4) expression and promoter activity but was associated with reduced GLUT1 
(SLC2A1) expression. There was no change in PGC-1α (PPARGC1A) expression. The 
effects of HDAC5 knockdown on glucose metabolism were not due to alterations in 
the initiation of differentiation, as knockdown of HDAC5 after the onset of 
differentiation also resulted in increased glucose uptake and insulin-stimulated 
glycogen synthesis. These data show that inhibition of HDAC5 enhances metabolism 
and insulin action in muscle cells. As these processes in muscle are 
dysregulated in metabolic disease, HDAC inhibition could be an effective 
therapeutic strategy to improve muscle metabolism in these diseases. Therefore, 
we also examined the effects of the pan HDAC inhibitor, Scriptaid, on muscle 
cell metabolism. In myotubes, Scriptaid increased histone 3 acetylation, GLUT4 
expression, glucose uptake and both oxidative and non-oxidative metabolic flux. 
Together, these data suggest that HDAC5 regulates muscle glucose metabolism and 
insulin action and that HDAC inhibitors can be used to modulate these parameters 
in muscle cells.