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Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We fed 6\u2010week\u2010old male C57BL\/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high\u2010fat\u2010diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AX\u2010treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (<jats:italic>p<\/jats:italic>&lt; 0.05). AX\u2010treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic\u2013euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA\u2010mediated AMPK\u2010depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK\u2010depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise\u2010induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12530","type":"journal-article","created":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T10:14:09Z","timestamp":1580465649000},"page":"241-258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":159,"title":["Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway"],"prefix":"10.1002","volume":"11","author":[{"given":"Yasuhiro","family":"Nishida","sequence":"first","affiliation":[{"name":"First Department of Internal Medicine University of Toyama  Toyama Japan"},{"name":"Fuji Chemical Industries, Co., Ltd.  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