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

Abstract

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.

Physiological effects of tangeretin and heptamethoxyflavone on obese C57BL/6J mice fed a high‐fat diet and analyses of the metabolites originating from these two polymethoxylated flavones

“…Adipose tissue macrophages are major sources of proinflammatory cytokines, such as TNF‐α, IL‐6, and IL‐1ß, and the inhibition of adipose macrophage cytokine production by TAN and HMF, as well as by other PMFs, has been previously reported (Funaro et al., 2016; Shin et al., 2017). TAN has also been shown to enhance skeletal mitochondrial biogenesis by activating the AMPK‐PGC1‐a pathway which potentially inhibits the progression of metabolic syndrome and type‐2 diabetes in mammals (Kou et al., 2018). Our study provides evidence suggesting that HMF attenuates hepatic damage and steatosis caused by HFDs, with concurrent reductions in oxidative stress.…”

“…These effects have been attributed to bioactive compounds in fruits and vegetables, and for citrus, these beneficial compounds largely include two main classes of flavonoids: the flavanone glycosides (i.e., hesperidin and naringin) and the more lipophilic polymethoxylated flavones (PMFs). Tangeretin (4',5,6,7,8‐pentamethoxyflavone; TAN) and heptamethoxyflavone (3',4',3,5,6,7,8‐heptamethoxyflavone; HMF) are among several of the PMFs that have been widely studied for their anti‐inflammatory and antioxidant properties (Arab et al., 2016; Assini et al., 2013; Kou et al., 2018; Lai et al., 2013; Lee et al., 2010, 2016; Liu et al., 2019; Manthey & Bendele, 2008). Inflammation and oxidative damage driven by stimulated macrophages in adipose tissue are major contributors to the development of metabolic syndrome and diabetes, and due to this, inhibition of macrophage‐driven inflammation is an important target in the discovery of compounds capable of combatting obesity‐associated diseases (Itoh et al., 2011).…”

Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

“…The effect was again PGC-1α, NRF, and SIRT1 dependent. More recent studies have shown PGC-1α-, SIRT1-, and/or AMPK-dependent effects of myricetin and tangeretin on mitochondrial biogenesis in murine skeletal muscles and of isoharmnetin in adipocytes [171][172][173]. In addition, flavonoid-induced protection has been demonstrated in various models of human diseases.…”

Nano Porous Carbon Derived from Citrus Pomace for the Separation and Purification of PMFs in Citrus Processing Wastes

“…Polymethoxyflavones are a group of flavonoids that exist widely in citrus fruits, particularly in the peels of Citrus reticulata Blanco and Citrus sinensis Osbeck—always wasted as CPW—which possess the highest amounts of PMFs compared to other edible parts of the fruit [ 11 , 12 ]. Compared with other flavonoids in CPW, PMFs present a better bioavailability and have been studied for improving skeletal muscle mitochondrial biogenesis, for their anti-diabetes and weight control effects, and for their antioxidant activity [ 13 , 14 ]. More importantly, PMFs have gradually been used to prevent and treat various human chronic diseases [ 15 ], or as bioavailability enhancers to enhance the biological activity of drugs [ 16 ].…”