Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway

Abstract

Background Skeletal muscle is mainly responsible for insulin‐stimulated glucose disposal. 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. Methods We fed 6‐week‐old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high‐fat‐diet (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. Results AX‐treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX‐treated 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–euglycemic 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‐mediated AMPK‐depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK‐depleted 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‐induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. Conclusions We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.

Impact of Astaxanthin on Diabetes Pathogenesis and Chronic Complications

“…In this study, ASX administration significantly ameliorated insulin resistance and glucose intolerance through the regulation of 5 adenosine monophosphate-activated protein kinase (AMPK) activation in the muscle, independent of its antioxidant activity. In addition, it stimulated muscle mitochondrial biogenesis [73].…”

“…Moreover, ASX potentiates post-receptor insulin signaling events by enhancing the autophosphorylation of insulin receptor-β (IR-β), IRS-1 associated PI3-kinase step, phospho-Akt/Akt ratio, and GLUT-4 translocation in skeletal muscles [72]. Yasuhiro Nishida et al also showed improved glucose metabolism by enhancing glucose incorporation into skeletal muscles in ASX-treated HFD mice [73]. In this study, ASX administration significantly ameliorated insulin resistance and glucose intolerance through the regulation of 5 adenosine monophosphate-activated protein kinase (AMPK) activation in the muscle, independent of its antioxidant activity.…”

<p>Network Pharmacology Combined with Transcriptional Analysis to Unveil the Biological Basis of Astaxanthin in Reducing the Oxidative Stress Induced by Diabetes Mellitus</p>

“…This is consistent with a previous study showing that Ast treatment significantly enhanced insulin-stimulated phosphorylation of the Akt protein in high fat diet-fed mice. 12 Accordingly, Ast functions in promoting both transcription of IRS3and phosphorylation of the downstream protein Akt, which together contributed to the improved insulin sensitivity in the Ast-treated groups. We also observed that the CD36 gene, which functions in mitochondrial β-oxidation and free fatty-acid transport in the AMPK-signaling pathway, was expressed at much higher levels in the Ast-treated DM rats than the DM control rats ( Figure 5C).…”

“…11 Oxidative stress in streptozotocin (STZ)-induced DM rats is inhibited by combination treatment of Ast with α-tocopherol. 12 Figure 1 (A) Chemical structure of Ast; (B) pipeline for identification of both predicted and detected Ast targets that integrate compound proteins, disease proteins, RNAseq analysis, GO analysis, docking, and network construction. Recently, Ast treatment has been reported to be involved in stimulating mitochondrial biogenesis and significantly ameliorating insulin resistance through activation of the AMPK pathway in skeletal muscle.…”

Isoproterenol-Induced Permeability Transition Pore-Related Dysfunction of Heart Mitochondria Is Attenuated by Astaxanthin

“…A similar effect of AST was shown for cancer [ 49 ]. Partial prevention of elimination of the components of the damaged respiratory chain complexes in ISO-injected rats ( Figure 2 ) may be related to the stimulation of mitochondrial biogenesis by AST [ 50 ].…”