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    Home > Active Ingredient News > Endocrine System > Sub-Journal of "Science": Run more, don't look for diabetes!

    Sub-Journal of "Science": Run more, don't look for diabetes!

    • Last Update: 2022-01-09
    • Source: Internet
    • Author: User
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    Life lies in exercise, exercise maintains health
    .

    The prevalence of metabolic diseases such as insulin resistance and type 2 diabetes in modern society is closely related to the general lack of human labor and exercise [1]
    .

    However, the role of lack of exercise in the pathophysiology of type 2 diabetes and how exercise can improve insulin resistance still puzzles the majority of medical researchers
    .

    Not long ago, Science Advances, a sub-issue of the top international journal "Science", published a major research result in the field of endocrinology and sports medicine by Professor Tony Tiganis of Monash University in Australia[2]
    .

    They found that exercise promotes ROS-mediated adaptive response by inducing skeletal muscle NOX4 expression, thereby enhancing muscle function, maintaining redox balance, and reversing insulin resistance
    .

    This discovery reveals in detail the mechanism by which exercise maintains blood sugar health from the perspective of oxidative stress, and provides a potential therapeutic target for insulin resistance related to aging and obesity
    .

    ▲Science Advances website This paper has a number of animal experiments and population experiments in the past to confirm that exercise can promote mitochondrial production and increase insulin sensitivity [3]
    .

    Some studies believe that this is related to the generation of ROS caused by exercise and the activation of the KEAP1/NFE2L2 pathway
    .

    ROS is a natural by-product of cell respiration, including H2O2, O2•− and•OH, etc.
    , and it is the endogenous oxidant of cells
    .

    The production of ROS during exercise is mainly catalyzed by the NOX family.
    Among them, NOX4 is located in skeletal muscle cells and can directly produce H2O2 and O2•−
    .

    After exercise, ROS oxidizes KEAP1, causing the transcription factor NFE2L2 that binds to KEAP1 to be released into the nucleus, promoting the expression of mitochondrial-related genes and antioxidant defense system genes
    .

    However, so far, the detailed mechanism has not been fully elucidated
    .

    Therefore, the Tiganis team used NFE2L2 and NOX4 as a breakthrough point.
    First, they tested the changes in the skeletal muscles of mice and humans before and after exercise, and found that the expression of NFE2L2 and NOX4 was up-regulated after exercise
    .

    Considering that NFE2L2 can bind to the NOX4 promoter region, the researchers concluded that NOX4 is the target gene of NFE2L2, and exercise promotes NOX4 expression by up-regulating NFE2L2
    .

    In order to prove this hypothesis, the Tiganis team used NFE2L2's activator-radish (lái fú, radish) sulfane instead of exercise to stimulate NFE2L2, and conducted cell and animal experiments to observe the expression of NOX4
    .

    They found that after myoblasts and mice were treated with sulforaphane, NOX4 expression increased; after knocking out NFE2L2, sulforaphane treatment could not increase NOX4 expression
    .

    This result verified their conjecture
    .

    Subsequently, the Tiganis team studied the effect of NOX4 loss in skeletal muscle on ROS production and found that after NOX4 in myoblasts was knocked out, H2O2 production was reduced, and H2O2 excitation and production during exercise was also eliminated
    .

    This proves that skeletal muscle NOX4 is necessary for ROS generation
    .

    In addition, after specifically knocking out NOX4 in mouse skeletal muscle, while ROS production is reduced, exercise capacity and exercise endurance are also significantly reduced.

    .

    So what is the relationship between reduced ROS generation and reduced exercise capacity? Considering that the oxidoreductase GPX-1 can eliminate ROS by reducing H2O2, the Tiganis team silenced the GPX-1 gene of NOX4 knockout mice to offset the reduction in ROS caused by NOX4 knockout
    .

    They found that after knocking out GPX-1, the locomotor ability and endurance of NOX4 knockout mice returned to normal with H2O2 levels
    .

    Therefore, skeletal muscle NOX4 knockout impairs exercise performance by reducing H2O2 production
    .

    ▲ Figure E: The production of H2O2 is reduced after NOX4 is knocked out, and it can be restored after knocking out GPX-1; Figures F and G: The production of mouse motor ability is reduced after NOX4 is knocked out, and it can be restored after knocking out GPX-1
    .

    (Nox4fl/fl is the wild-type mouse for control, Mck-Cre; Nox4fl/fl is the NOX4 knockout mouse in the experimental group skeletal muscle, Mck-Cre; Nox4fl/fl, Gpx1-/- is the skeletal muscle GPX-1 and NOX4 in the experimental group Double knockout mice) Previous studies have shown that the strength of exercise capacity is related to the content of skeletal muscle mitochondria [4]
    .

    Therefore, the Tiganis team compared the expression of related genes in the skeletal muscle of GPX-1 and NOX4 double knockout mice, NOX4 knockout mice and normal mice, and found mitochondrial genes (Pcg1a, Nrf1, Nrf2 and Tfam) and genes related to the mitochondrial respiratory chain , The expression decreases after NOX4 is knocked out, and when GPX-1 is knocked out on the basis of NOX4 knock out, the expression recovers
    .

    This result was also verified in NOX4 knockout myoblasts, proving that skeletal muscle NOX4 knockout inhibits mitochondrial production by reducing H2O2 levels, thereby impairing the exercise capacity of mice
    .

    In fact, studies have found that NFE2L2 is involved in exercise-induced mitochondria production, and the NFE2L2 activator sulforaphane can enhance the exercise capacity of mice
    .

    Therefore, the Tiganis team speculated that the reduction in exercise capacity caused by the reduction of mitochondrial production in NOX4 knockout mice may be related to the loss of NFE2L2
    .

    Using sulforaphane to treat NOX4 knockout mice, it was found that the decrease in NFE2L2 expression caused by NOX4 knockout was corrected and the decrease in mitochondrial-related gene expression was inhibited
    .

    The exercise endurance test found that the sulforaphane treatment rescued the decline of the exercise endurance of NOX4 knockout mice
    .

    These findings prove that skeletal muscle NOX4 knockout inhibits NFE2L2 by reducing H2O2, thereby weakening mitochondrial production and ultimately impairing exercise capacity
    .

    ▲ Figure AC: The expression of mitochondrial genes decreases after NOX4 knockout; Figures D and E: The expression of mitochondrial respiratory chain related genes decreases after NOX4 knockout; Figure F: Mitochondrial production decreases after NOX4 knockout (green fluorescence indicates mitochondrial density ) The Tiganis team noticed that skeletal muscle contraction produces ROS, which can enhance NFE2L2-mediated antioxidant defense [5]
    .

    Moreover, previous experiments have proved that NOX4 is necessary for muscle contraction to produce ROS
    .

    Therefore, Tiganis and his colleagues hypothesized that NOX4 is related to antioxidant defense, that is, the lack of NOX4 can lead to the deficiency of antioxidant defense
    .

    Cell and animal experiments have found that NOX4 knockout causes the decrease in the expression of NFE2L2 and NFE2L2 target genes, and eliminates the promotion of exercise on the expression of NFE2L2
    .

    Unbiased proteomics and WB confirmed that the expression of antioxidant defense genes decreased (mitochondrial SOD2, GCLM, PRDX6, NQO1, PRDX1 to PRDX3 and H2O2 enzymes), lipid peroxidation (4-HNE), protein oxidation and damage (protein carbonyl Oxidative damage such as cytotoxicity) and muscle damage (CK) increases
    .

    Knockout of GPX-1 on the basis of NOX4 knockout to inhibit the reduction of H2O2 can greatly rescue the decline in the expression of antioxidant defense genes and reduce the oxidative damage of skeletal muscle
    .

    Therefore, skeletal muscle NOX4 knockout inhibits NFE2L2 by reducing H2O2, thereby weakening the antioxidant defense and increasing oxidative damage
    .

    ▲ Figure E (WB), Figure F (unbiased proteomics) and Figure G and H (RT-PCR): detection of antioxidant defense genes after NOX4 knockout expression decreased; Figure I (4-HNE), Figure J (Protein carbonylation) and Figure K (CK): To detect the up-regulation of oxidative damage genes after NOX4 knockout.
    In view of the insulin resistance caused by aging and type 2 diabetes, it is related to oxidative damage
    .

    Based on the NOX4/H2O2/NFE2L2/antioxidant defense signal axis discovered in the above experiment, Tiganis and his colleagues further speculated that the insulin resistance of aging mice may be due to the decrease of NOX4 expression
    .

    The researchers compared the expression of NOX4 in aging mice and young mice and found that the expression of NOX4 in skeletal muscle of aging mice dropped by 46%! Later, the researchers also found that the blood sugar and insulin levels of NOX4 knockout mice increased after meals, the insulin response was weakened, the glucose uptake of skeletal muscles was reduced, and insulin resistance appeared
    .

    For NOX4 knockout mice, knocking out GPX1 to accumulate H2O2, or taking sulforaphane to activate NFE2L2, can reverse the insulin resistance in NOX4 knockout mice
    .

    Obesity can also promote insulin resistance by exacerbating oxidative stress throughout the body [6]
    .

    The Tiganis team found that NOX4 expression in the skeletal muscle of obese mice induced by diet was reduced by 44%! Therefore, they boldly speculate: NOX4 deficiency can exacerbate insulin resistance caused by diet-induced obesity
    .

    Tiganis and his colleagues evaluated the muscle development and glucose homeostasis of NOX4 knockout mice after a high-fat diet and found no changes in body weight, body composition, and muscle tissue morphology, but skeletal muscle mitochondria production decreased, insulin resistance increased, and glucose decreased.
    Increased tolerance, decreased glucose uptake capacity of skeletal muscle, decreased insulin signal transduction (decreased phosphorylation level of AKT at Ser473), and decreased insulin sensitization effect caused by exercise
    .

    ▲ Figure C and Figure E: Insulin tolerance test found that blood glucose levels increased after NOX4 knockout, and insulin response was weakened; Figure D: The phosphorylation level of AKT at Ser473 decreased after NOX4 knockout, and treated with sulforaphane (SILF) After recovery
    .

    Since the loss of mitochondrial SOD2 or the increase of ROS in mitochondria, it can reduce insulin signal transduction and promote insulin resistance
    .

    So, is the insulin resistance caused by the weakening of NOX4/H2O2/NFE2L2/antioxidant defense signal axis related to this? Tiganis and his colleagues first tested the myoblasts after NOX4 knockout and found that while the production of H2O2 and the expression of antioxidant defense genes decreased, the expression of mitochondrial SOD2 protein decreased, the O2•− inside the mitochondria increased, and protein carbonylation Increase and decrease the insulin signal
    .

    When NFE2L2 is activated with sulforaphane or knocking out KEAP1, protein carbonylation is reduced and insulin signal is restored
    .

    Using mitochondrial targeting antioxidants, SOD mimics, or mitochondrial targeting tetrapeptide SS31 to block mitochondrial O2•− production can also reduce protein carbonylation and restore defective insulin signaling
    .

    These results indicate that NOX4/H2O2/NFE2L2/antioxidant defense/mitochondrial oxidative stress signal axis plays an important role in the development of insulin resistance
    .

    ▲ Schematic diagram of the thesis mechanism.
    Scientific research is a treasure hunt based on the known and unknown, and it is also a jigsaw puzzle that completes the fragments based on clues
    .

    Digging for clues from the known clues, and then boldly verifying the hypothesis carefully, through delicately designed experiments, step by step, to clear the unknown fog, find the treasure of the phenotype, find the incomplete fragments, and fill the puzzle of the mechanism
    .

    This research by the Tiganis team is just that
    .

    However, the fly in the ointment is that the experiment is mainly carried out around NOX4 knockout, and the conclusion of the experiment is only based on the results of the loss of NOX4 function
    .

    It may be better to combine the perspective of NOX4 function enhancement, such as constructing a NOX4 skeletal muscle specific overexpression model at the same time, so as to explore and explain its role in the pathophysiology of mitochondrial production and insulin resistance from both sides
    .

    "Keep your mouth shut and open your legs", the second half of this six-character motto for preventing and treating diabetes is beyond imagination
    .

    So, for blood sugar health, don't move quickly! References [1] Cartee GD, Hepple RT, Bamman MM, Zierath JR.
    Exercise Promotes Healthy Aging of Skeletal Muscle.
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    Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance.
    Sci Adv.
    2021;7(51):eabl4988.
    doi:10.
    1126/sciadv.
    abl4988[3] Egan B, Zierath JR.
    Exercise metabolism and the molecular regulation of skeletal muscle adaptation.
    Cell Metab.
    2013;17(2):162-184.
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    012[4] Merry TL, Ristow M .
    Mitohormesis in exercise training.
    Free Radic Biol Med.
    2016;98:123-130.
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    032[5] Merry TL, Ristow M.
    Nuclear factor erythroid-derived 2-like 2 (NFE2L2 , Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice.
    J Physiol.
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