Adenosine and its derivatives improve exercise performance and exert anti-fatigue effects via AMPK/PGC-1α signaling pathway in mice

Studies of the AMPK/PGC-1α signaling pathway and exercise-induced metabolism have facilitated the development of anti-fatigue agents and exercise mimetics. In this work, adenosine and its 22 derivatives, typical of substitutions at the hydroxyl group of the sugar moiety, were firstly evaluated as anti-fatigue agents. In the running wheel tests, adenosine and most derivatives demonstrated a significant increase in the exhaustion distance when compared to the control group. Particularly, the optimized compound 2 exhibited a 3.1-fold increase in exhaustion distance compared to the positive control group treated with AICAR, and a remarkable 9.8-fold increase compared to the blank control group. Furthermore, improved performances were observed in weight-loaded swimming, high jumping, hanging wire, and tail suspension tests. Compound 2 not only reduced levels of lactic acid (LA) and blood urea nitrogen (BUN), but also preserved hepatic and muscle glycogen content during exercise. Notably, compound 2 activated AMPK/PGC-1α pathway without stimulating the central nervous system. Moreover, compound 2 demonstrated a favorable safety in vivo at a dose of 1.96 × 10-5 mol/kg for 21 days. This study unveils, for the first time, the ability of adenosine and its derivatives to resist exercise-induced fatigue, thereby providing promising lead compounds for the development of drugs aimed to prevent and treat fatigue-related diseases. Moreover, it sheds light on the potential therapeutic approaches utilizing endogenous substance.