During fasting, rapid metabolic adaptations, such as a shift from carbohydrate to lipid oxidation, are required to maintain whole-body energy homeostasis. This mainly occurs by tissue-specific coordinated regulation of several nutrient and energy-sensitive pathways. Animal studies suggest that activation of the AMP-activated kinase (AMPK) triggers transcriptional modulation of genes involved in lipid and glucose metabolism. Sirtuin-1 (SIRT1) and histone deacetylase 4 (HDAC4) were recently proposed to play a central role in this AMPK-mediated transcriptional regulation of energy metabolism. Our aim is therefore to investigate the effects of fasting on AMPK/SIRT1/HDAC4 signaling pathways in human skeletal muscle.