Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway
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Insulin resistance in skeletal muscle is a key feature in the pathogenesis of type 2 diabetes (T2D) that often manifests early in its development. Pharmaceutical and dietary strategies have targeted insulin resistance to control T2D, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of T2D. Dihydromyricetin (DHM) is a natural flavonol which provides a wide range of health benefits including anti-inflammatory and anti-tumor effects. However, little information is available regarding the effects of DHM on skeletal muscle insulin sensitivity as well as the underlying mechanisms. In the present study, we found that DHM activated insulin signaling and increased glucose uptake in skeletal muscle in vitro and in vivo. The expression of light chain 3, the degradation of sequestosome 1, and the formation of autophagosomes were also upregulated by DHM. DHM-induced insulin sensitivity improvement was significantly abolished in the presence of 3-methyladenine, bafilomycin A1, or Atg5 siRNA in C2C12 myotubes. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and Sirt3 in skeletal muscle in vitro and in vivo. Autophagy was inhibited in the presence of Sirt3 siRNA in C2C12 myotubes and in skeletal muscles from Sirt3−/− mice. Additionally, PGC-1α or AMPK siRNA transfection attenuated DHM-induced Sirt3 expression, thereby abrogating DHM-induced autophagy in C2C12 myotubes. In conclusion, DHM improved skeletal muscle insulin sensitivity by partially inducing autophagy via activation of the AMPK-PGC-1α-Sirt3 signaling pathway.
KeywordsSirt3 Autophagy Dihydromyricetin Skeletal muscle insulin sensitivity Type 2 diabetes
Protein kinase B
AMP-activated protein kinase
Insulin receptor substrate-1
Light chain 3
Peroxisome proliferator-activated receptor coactivator-1α
Small interfering RNA
Type 2 diabetes
Silent mating-type information regulation 2 homolog 3
This work was supported by the research Grant from National Natural Science Foundation of China (81372975) and the special fund of Chongqing key laboratory (CSTC) for Nutrition and Food Safety.
Conflict of interest
The authors declare no conflicts of interest.
- 11.D. Zou, K. Chen, P. Liu, H. Chang, J. Zhu, M. Mi. Med. Sci. Sports Exerc. (2014)Google Scholar