Histone Deacetylase inhibitors modulate mitochondrial biogenesis in skeletal muscle

The control of metabolic pathways occurs at the transcriptional level also through epigenetic mechanisms. Since it has been demonstrated that Histone Deacetylases (HDACs) are involved in muscle fiber type determination, our aim was to investigate the metabolic effects following the biochemical inhibition of HDACs in skeletal muscle and the underlying mechanisms. In C2C12 myotubes we observed that HDAC inhibitors (HDACi) upregulate the mRNA of PGC-1alpha and its target genes. Additionally, transcriptome analysis in C2C12 treated with HDACi revealed an increase in OXPHOS genes and in genes coding for fatty acids catabolism enzymes, most likely linked to PGC-1alpha-dependent activation of gene transcription. Consistent with the increase of PGC-1alpha, FACS analysis revealed increased density and activity of mitochondria in C2C12 myoblasts. As well, staining of myotubes treated with HDACi showed an increase in mitochondrial density and activity. Using Class specific HDAC inhibitors we observed that Class I HDACs are the most involved in the promotion of these effects. These results underscore a central role of HDACs, and most probably of Class I HDACs, in modulating metabolic adaptation in cells and suggest HDACi as valuable tools to study molecular mechanisms implicated in energy metabolism and possibly in metabolic diseases. (Funded by grants: EC FP6 LSHM-CT-2006-037498 SOUTH, PRIN 2008 ZTN724)