Exogenous ATP-induced lipolysis and its correlation with skeletal muscle atrophy and hepatic damage in fasting mice

Adenosine triphosphate (ATP) is a critical energy currency in living organisms, yet its extracellular transport and efficacy as an exogenous energy source remain controversial. This study explored the effects of exogenous ATP administration on energy metabolism and tissue integrity in fasting mice. C57BL/6J mice were intraperitoneally injected with ATP at doses of 25, 50, and 100 mg/kg every 12 h during a 72-h fasting period. While ATP did not significantly alter body weight, higher doses elevated blood ketone and free fatty acids levels with reducing lactate concentrations. At the tissue level, ATP exacerbated fasting-induced fat loss and aggravated skeletal muscle atrophy, as evidenced by reducing gastrocnemius muscle fiber cross-sectional areas and increasing expression of atrophy markers F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1 (Murf-1). Additionally, high-dose ATP (100 mg/kg) significantly increased plasma levels of liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating hepatic damage. RNA sequencing and Western blot analyses revealed that ATP administration reduced lipid synthesis and enhanced lipolysis, leading to elevated free fatty acid levels in plasma and tissues. These findings suggest that exogenous ATP fails to improve energy metabolism during fasting and may instead promote lipolysis, thereby exacerbating skeletal muscle atrophy and hepatic injury. The study highlights the potential adverse effects of exogenous ATP under fasting conditions, emphasizing the need for further investigation into its mechanisms and clinical implications.