Citrus Tangeretin Improves Skeletal Muscle Mitochondrial Biogenesis via Activating the AMPK-PGC1-α Pathway In Vitro and In Vivo: A Possible Mechanism for Its Beneficial Effect on Physical Performance

Mitochondrial biogenesis is a key factor, which influences the function of skeletal muscle. Increasingly, flavonoids are reported to have the potential ability of regulating mitochondrial biogenesis. In this study, we investigated the effects of tangeretin, a polymethoxylated flavonoid isolated from mandarin fruits, on mitochondrial biogenesis and its underlying mechanisms. The tangeretin was obtained from the peel of "Dahongpao" tangerine by macroporous adsorptive resins combined with preparative-high performance liquid chromatography. The activity of mitochondrial biogenesis was explored by using mouse-derived C2C12 myoblasts and Kunming mice. Results showed that the purity of tangeretin obtained was 98.64%, and it could effectively activate mitochondrial biogenesis signaling pathway both at gene and at protein levels in C2C12 myoblasts. Animal experiments showed that tangeretin pretreatment could markedly improve exercise performance (the time of hanging wire and run to fatigue was obviously increased 1.6-fold and 2.1-fold in the high-dose tangeretin group, respectively), and the transmission electron microscopy, Western blotting, and immunohistochemistry further indicated that tangeretin increased mitochondria number and activated mitochondrial biogenesis signaling axis. Our findings suggest that tangeretin enhanced mitochondrial biogenesis via activating the AMPK-PGC1-α pathway, resulting in the improvement of exercise performance, and tangeretin may be a potentially novel mitochondria regulator in foods.