Gallic Acid Ameliorates Skeletal Muscle Metabolic Inflexibility by Regulating Lactate Metabolism and Promoting Mitochondrial Function

ABSTRACT Obesity‐induced mitochondrial dysfunction impairs skeletal muscle metabolic flexibility. Gallic acid possesses the ability to modulate metabolic homeostasis. This study aimed to investigate the impact of gallic acid on high‐fat diet (HFD)‐induced metabolic disorders in skeletal muscle. Twenty‐four mice were randomly divided into three groups and subjected to HFD and gallic acid intervention for 12 weeks. The overall glycolipid metabolic status, exercise performance, muscle fiber type, and antioxidant capacity of skeletal muscle in HFD‐fed mice treated with gallic acid were assessed. Untargeted metabolomics analysis was performed to evaluate key metabolic characteristics in skeletal muscle. Gallic acid administration effectively reduced fat accumulation, improved exercise capacity, and enhanced antioxidant capacity in HFD‐fed mice. Untargeted metabolomics revealed that gallic acid positively regulated lactate metabolism and mitochondrial fatty acid oxidation. Mechanistically, gallic acid intervention increased fatty acid oxidation capacity while inhibiting lactate production and mitochondrial protein lactylation in skeletal muscle. Moreover, the role of gallic acid in enhancing mitochondrial function through the LDHA‐lactate axis has been demonstrated in C2C12 cells. Collectively, gallic acid ameliorated HFD‐induced metabolic disorders in skeletal muscle, indicating a novel role for gallic acid in ameliorating diet‐induced skeletal muscle metabolic disorders by regulating lactate metabolism and mitochondrial function.