Anti-fatigue and antioxidative effects of amino acid (Leu, Gln, Cys)-EGCG complex via NRF2 and PGC-1α pathways: insights from cellular, animal, and pilot clinical studies

BACKGROUND/OBJECTIVES: Fatigue is closely associated with an impaired mitochondrial function, oxidative stress, and inefficient energy metabolism, all contributing to reduced physical performance. Nutritional strategies targeting mitochondrial biogenesis and antioxidant defense may help alleviate fatigue and enhance endurance. This study examined the anti-fatigue and antioxidant effects of an amino acid (AA)-epigallocatechin gallate (EGCG) mixture comprised of 3 AAs (cysteine [Cys], glutamine [Gln], and leucine [Leu]) and EGCG on mitochondrial biogenesis, oxidative stress mitigation, and physical performance enhancement. MATERIALS/METHODS: C2C12 myoblasts were treated to assess mitochondrial biogenesis-related gene expression and oxidative stress markers. Animal studies measured the swimming endurance, glycogen, adenosine triphosphate (ATP), and serum parameters. A pilot clinical trial evaluated the blood glucose, lactate, and serum enzyme levels post-exercise. RESULTS: In cellular experiments, a 1:1:3 ratio of the AA mixture (Cys, Gln, and Leu) with EGCG enhanced mitochondrial biogenesis-related gene expression (AMP-activated protein kinase, sirtuin 1, and peroxisome proliferator-activated receptor gamma coactivator 1α [PGC-1α]) and reduced the oxidative stress markers (reactive oxygen species and malondialdehyde [MDA]). Animal studies revealed significant increases in swimming endurance, elevated glycogen and ATP levels, and reduced serum fatigue markers (creatine phosphokinase, lactate dehydrogenase, and blood nitrogen). Furthermore, nuclear factor erythroid 2-related factor 2 (NRF2) and PGC-1α expression was significantly upregulated in the gastrocnemius muscle, supporting enhanced mitochondrial function. In addition, the antioxidant effects were observed with reduced MDA levels in liver tissue. Clinical trial data showed improved blood lactate clearance and higher post-exercise blood glucose levels in the AA-EGCG group compared to the placebo group. CONCLUSION: The AA-EGCG mixture enhances mitochondrial biogenesis and antioxidant capacity by activating the NRF2 and PGC-1α pathways, improving physical performance and reducing fatigue. This study highlights its potential as a supplement for managing fatigue and enhancing endurance.