Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle

Makino, Hírofumi; Takayama, Hiroaki; Saito, Yoshiro; Mita, Yuichiro; Kikuchi, Akihiro; Ishii, Kiyo aki; Chikamoto, Keita; Kanamori, Taro; Tajima, Natsumi; Lan, Fei; Takeshita, Yumie; Honda, Masao; Tanaka, Misuzu; Kato, Seiji; Matsuyama, Naoto; Yoshioka, Y.; Iwayama, Kaito; Tokuyama, Kumpei; Akazawa, Nobuhiko; Maeda, Seiji; Takekoshi, Kazuhiro; Matsugo, Seiichi; Noguchi, Noriko; Takamura, Toshinari

doi:10.1038/nm.4295

Cited by 133 publications

(139 citation statements)

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“…AX is a strong antioxidant and could scavenge physiological reactive oxygen species (ROS) generated during exercise training, thereby canceling the beneficial effects of exercise with regard to endurance and glucose tolerance. Previous reports have also suggested that an exercise tolerance test is important to assess the metabolic adaptations in muscle and exercise‐induced ROS generation have beneficial effect on metabolic adaptation in muscle . Thus, we next examined whether AX affected the training‐induced increase in exercise tolerance.…”

Section: Resultsmentioning

confidence: 98%

“…It is possible that AX somehow sequesters ROS that cause damage, but not the ROS that induce beneficial effects. Previous reports suggested that exercise‐induced generation of ROS not only causes oxidative damage, but that the ROS also function as signaling molecules to facilitate beneficial molecular adaptations . To rule out the possibility that AX might mitigate the ROS‐mediated positive effects of exercise training by activating several molecules, including AMPK and PGC‐1α, in the muscle, we examined whether AX had any effect on H 2 O 2 ‐induced AMPK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

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

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

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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.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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

Nishida

Nawaz

Kado

et al. 2020

J cachexia sarcopenia muscle

Self Cite

110

125

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“…Interestingly, activated AMPK stimulates PGC1 α gene expression in response to endurance exercise (Misu et al. ). It is still unclear whether activation and interaction of these signal transductions are distinct between slow‐ and fast‐ twitch fibers upon denervation.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, AMP-activated protein kinase (AMPK) enhances FoxO3 transcriptional activity when FoxO3 is translocated into nucleus (Greer et al 2007), whereas peroxisome-proliferator-activated receptor-c coactivator-1 alpha (PGC1a) inhibits FoxO3 function (Sandri et al 2006). Interestingly, activated AMPK stimulates PGC1a gene expression in response to endurance exercise (Misu et al 2017). It is still unclear whether activation and interaction of these signal transductions are distinct between slow-and fast-twitch fibers upon denervation.…”

Section: Introductionmentioning

confidence: 99%

Distinct signal transductions in fast- and slow- twitch muscles upon denervation

Gao

2018

Physiol Rep

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Denervation induces skeletal muscle atrophy, which primarily impairs oxidative slow twitch fibers. The underlying mechanism of this phenomenon, however, remains to be addressed. We hypothesize that denervation‐induced fiber‐specific atrophy may result from the distinct activities of different signaling pathways that are involved in protein synthesis and degradation in fast‐ and slow‐twitch fibers. In this study, 1‐month‐old male mice were subjected to unilateral sciatic denervation for 4 days. Fast‐twitch muscle extensor digitorum longus (EDL) and slow‐twitch muscle soleus were collected from the denervated side and the control side of hind limbs. Total and phosphorylated protein levels of key factors of major signaling pathways in these tissues were determined using western blot assay. Our data showed that total AKT and FoxO3 protein levels were upregulated in denervated muscles as compared with control sides. Phosphorylation of AKT and FoxO3 were proportionally enhanced in denervated EDL but not soleus, indicating AKT activation drives phosphorylation of FoxO3 in EDL but not in soleus upon denervation. As a result, FoxO3‐targeted atrogenes MurF1 and Atrogin1 protein abundances were reduced in denervated EDL but not altered in soleus. In consistent with this change, polyubiquitination were significantly increased in denervated soleus, but only a slight increase in ubiquitination was found in denervated EDL. Autophagy marker LC3 protein level was significantly increased in both muscle types, but in greater extent in EDL after denervation. IRS1 protein level and active ERK were reduced in both muscles upon denervation, which might contribute to the upregulation of total AKT protein level and FoxO3 abundance in EDL and soleus. Total and phosphorylated AMPK protein levels were increased in denervated soleus but not in EDL. Overall, these data reveal that the key signaling pathways that regulate protein synthesis and degradation are more sensitive in soleus than EDL in response to denervation.

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“…We have previously reported that SeP serves as a hepatokine, promoting glucose intolerance and insulin resistance in type 2 diabetes. 5) SeP is upregulated in the liver of type 2 diabetes patients, and high levels of SeP impair insulin signaling and glucose metabolism in both liver and muscle of mice. 5) We have recently reported that SeP is involved in exercise resistance by suppressing the levels of exercise-induced reactive oxygen species (ROS) in skeletal muscle.…”

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confidence: 99%

Comparison of Human Selenoprotein P Determinants in Serum between Our Original Methods and Commercially Available Kits

Saito

Makino

Takayama

et al. 2018

Biological & Pharmaceutical Bulletin

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Selenoprotein P (SeP) is a selenium (Se)-rich extracellular protein. SeP is identified as a hepatokine, causing insulin resistance in type 2 diabetes. Thus, the measurement of SeP in serum has received much attention, and several enzyme-linked immunosorbent assay (ELISA) kits for SeP determination are now commercially available. In the present study, we determined the serum SeP levels by our original ELISA and sol particle homogeneous immunoassay (SPIA) methods and also by commercially available kits, and these determinants were compared. We found a kit-dependent correlation of the determinants with our methods. These results suggest that the selection of kit is critical for comparison with our previous reports and for discussing the relationship between the serum SeP levels and disease condition.

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Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle

Cited by 133 publications

References 57 publications

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

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

Distinct signal transductions in fast- and slow- twitch muscles upon denervation

Comparison of Human Selenoprotein P Determinants in Serum between Our Original Methods and Commercially Available Kits

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