title: Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway.
abstract: 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.
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Linying
authors.initials: L
authors.lastname: Shi
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Xianglong
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Ran
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
authors.forename: Qianyong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China. zjdnfs@126.com.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China. mantianmi2012@163.com.
authors.forename: Mantian
authors.identifier: http://orcid.org/0000-0002-2592-6032
authors.initials: M
authors.lastname: Mi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D044948:Flavonols / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018482:Muscle, Skeletal / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects*; D056566:Sirtuin 3 / Q000187:drug effects*; D014157:Transcription Factors / Q000187:drug effects*
chemical_list: D044948:Flavonols; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C525046:Sirt3 protein, mouse; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3; C472036:dihydromyricetin
keywords: Autophagy; Dihydromyricetin; Sirt3; Skeletal muscle insulin sensitivity; Type 2 diabetes