In 1966 the two Swedish scientists Bergström and Hultman elegantly demonstrated the glycogen super-compensation phenomenon in human skeletal muscle. By use of one-legged exercise it was revealed that the ability to super-compensate muscle glycogen is restricted to the prior exercised muscle. The authors concluded that a single bout of exercise induces local changes within the muscle that are maintained for several days after exercise increasing the set-point for glucose storage. It is noteworthy that the nature of this exercise-induced signature still remains to be established. We have now performed invasive human study alongside mechanistic studies of transgenic animals enabling us to provide a model for the molecular signature induced by exercise ensuring that skeletal muscle glycogen content is re-established and even super-compensated. Our studies point to an important regulatory role of the energy/fuel sensing kinase; AMP-activated protein kinase.