Hydroxycitrate delays early mortality in mice and promotes muscle regeneration while inducing a rich hepatic energetic status

ATP citrate lyase (ACLY) inhibitors have the potential of modulating central processes in protein, carbohydrate, and lipid metabolism, which can have relevant physiological consequences in aging and age‐related diseases. Here, we show that hepatic phospho‐active ACLY correlates with overweight and Model for End‐stage Liver Disease score in humans. Wild‐type mice treated chronically with the ACLY inhibitor potassium hydroxycitrate exhibited delayed early mortality. In AML12 hepatocyte cultures, the ACLY inhibitors potassium hydroxycitrate, SB‐204990, and bempedoic acid fostered lipid accumulation, which was also observed in the liver of healthy‐fed mice treated with potassium hydroxycitrate. Analysis of soleus tissue indicated that potassium hydroxycitrate produced the modulation of wound healing processes. In vivo, potassium hydroxycitrate modulated locomotor function toward increased wire hang performance and reduced rotarod performance in healthy‐fed mice, and improved locomotion in mice exposed to cardiotoxin‐induced muscle atrophy. Our findings implicate ACLY and ACLY inhibitors in different aspects of aging and muscle regeneration. ATP citrate lyase (ACLY) inhibitors have been proposed as calorie restriction mimetics. We performed a longevity assay in mice using the ACLY inhibitor hydroxycitrate. We observed that hydroxycitrate delays early mortality, having pleiotropic effects in muscle and liver physiology. Hydroxycitrate produced an energy‐rich status in the liver, while modulated pathways involved in muscle regeneration and potentiated locomotor function in mice challenged with the myonecrotic agent carditoxin.