Fig. 1.

AMPK regulates muscle transcriptional events through distinct mechanisms. Activation of AMPK upon energy stress increases mitochondrial and oxidative metabolism gene expression through direct and indirect events. SIRT1 is an example of a transcriptional regulator whose activity is increased by AMPK through an indirect mechanism (i.e., by promoting an increase in NAD+). Direct phosphorylation of AMPK occurs, for example, on the coactivator PGC-1α and the FOXO family of transcription factors, whose subsequent deacetylation by SIRT1 increases their activity. The activation of PGC-1α leads to the coactivation of a myriad of transcription factors, such as PPARα, PPARβ/δ and CREB, which is also phosphorylated and activated by AMPK. Phosphorylation of GEF promotes co-translocation with MEF2 to the nucleus. Furthermore, phosphorylation of HDAC5 by AMPK relieves the inhibition on the MEF2/GEF complex and allows transcriptional activation. These examples illustrate the mechanisms involved when AMPK directly and indirectly regulates transcriptional events