Hesperetin Improves Fatigue and Endurance Performance in Mice by Increasing Muscle Synthesis Via the Protein Kinase B/Mechanistic Target of Rapamycin Signaling Pathway.

BACKGROUND: Fatigue is a common and complex phenomenon resulting from the disruption of 1 or more physiological processes that facilitate muscle fibers in generating force. It is a significant public health concern affecting human health globally. Research indicates that natural compounds may effectively and safely alleviate physical fatigue due to their potential health benefits and minimal side effects.

OBJECTIVES: The objective of this study was to investigate the ergogenic effect of citrus flavonoid hesperetin (HES).

METHODS: This study utilized a multifaceted approach involving network pharmacology, molecular docking, in vitro, and in vivo analyses.

RESULTS: Our results revealed that HES may act on multiple targets and pathways to ameliorate fatigue. Molecular docking analysis showed that AKT1 was the most potent target for HES in relieving fatigue. In addition, histologic immunostaining analysis revealed that HES enhanced the size of myofibers by elevating the expression of type I and type II myofibers through the Protein Kinase B/Mechanistic Target of Rapamycin (AKT/mTOR) signaling pathway in C2C12 myotubes and mouse gastrocnemius muscle. Besides, HES increased the strength and endurance of mice by increasing grip strength, running time, and exhaustion time. These results indicate that HES is a potential natural compound to alleviate fatigue and improve exercise performance.

CONCLUSIONS: This study provides a novel natural compound for alleviating physical fatigue. Due to its role in skeletal muscle synthesis, HES could be a potential candidate for skeletal muscle disorders like sarcopenia. The potential role of HES in addressing sarcopenia requires further investigation.