Suppression or abnormalities of skeletal muscle function caused by disuse, aging and certain diseases are associated with increased oxidative stress and inflammatory response. Avenanthramides (Avns), the polyphenol compounds only found in oats, exhibit anti-inflammatory effects by inhibiting NFκB activation in select cell lines. However, the molecular mechanism by which Avns reduces inflammation in skeletal muscle cell is still unclear. PURPOSE: The purpose of this study was to investigate (1) whether Avns suppress inflammatory responses in skeletal muscle cells; and (2) the molecular mechanism by which Avns can inhibit NFκB activation. METHODS: C2C12 mouse skeletal muscle cell lines were treated with 200μM tert-Butyl hydroperoxide (tBHP) for 6h with or without three different forms of Avns (AvnA, AvnB and AvnC). Interactions between Avns and IκB kinase (IKKβ) were tested by protein-ligand docking and protein kinase assay. NFκB-mediated inflammatory pathways were evaluated. RESULTS: The docking score correlated with IKKβ in vitro activity suggesting Avns are synergistic bioinhibitors for IKKβ pathway. Avns reduced the kinase activity in response to tBHP treatment. TNF-α and IL-1β mRNA levels were increased by 6.2- and 13-fold (P<0.01), respectively, with tBHP compared to control, but these levels were reduced by approximately 2-fold with Avns (P<0.01). IκB protein degradation and NFκB luciferase assay, used as a marker of NFκB activation, showed that Avns suppressed tBHP-induced NFκB activation (all P<0.01). Cyclooxygenase-2 (COX-2) protein expression was increased with tBHP, along with a 3.1-fold increase in COX-2 luciferase activity (P<0.01), but these markers were reduced by ~2-fold with Avns (P<0.01). Prostaglandin E2 (PGE2) level was increased 3.7-fold with tBHP treatment (P<0.01), but was decreased by 59, 54 and 62% (P<0.01), respectively, with AvnA,B,and C. CONCLUSIONS: Avns are potent inhibitors of NFκB-mediated inflammatory response due to the downregulation of IKKβ activity in C2C12 cells.
The microbiome has emerged as a key player contributing significantly to the human physiology over the past decades. The potential microbial niche is largely unexplored in the context of exercise enhancing capacity and the related mitochondrial functions. Physical exercise can influence the gut microbiota composition and diversity, whereas a sedentary lifestyle in association with dysbiosis can lead to reduced well-being and diseases. Here, we have elucidated the importance of diverse microbiota, which is associated with an individual’s fitness, and moreover, its connection with the organelle, the mitochondria, which is the hub of energy production, signaling, and cellular homeostasis. Microbial by-products, such as short-chain fatty acids, are produced during regular exercise that can enhance the mitochondrial capacity. Therefore, exercise can be employed as a therapeutic intervention to circumvent or subside various metabolic and mitochondria-related diseases. Alternatively, the microbiome–mitochondria axis can be targeted to enhance exercise performance. This review furthers our understanding about the influence of microbiome on the functional capacity of the mitochondria and exercise performance, and the interplay between them.
We studied the inhibitory effects of ginsenoside-Rb1 (1) on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transcriptional activation of the cyclooxygenase-2 (COX-2) promoter. The suppressive activity of ginsenoside-Rb1 was characterized using COX-2 promoter-driven luciferase reporter plasmids in a transient transfection system. Ginsenoside-Rb1 at 100 microM inhibited TPA-induced transcriptional activation of the COX-2 promoter. To identify the cis-acting elements responsible for this inhibition, the effects of site-specific mutations in the COX-2 promoter region were examined. Inhibition by ginsenoside-Rb1 was not affected by mutations in nuclear factor-kappaB- or cAMP-responsive elements. However, the effects were abolished when the nuclear factor-interleukin-6 binding site was mutated, indicating that ginsenoside-Rb1 exerts its effects via this element. In conclusion, ginsenoside-Rb1 inhibits TPA-induced COX-2 promoter activity through the nuclear factor interleukin-6 binding site and not through the nuclear factor-kappaB or cAMP-responsive elements.
Exposure to particulate matter (PM) causes mitochondrial dysfunction and lung inflammation. The cyclooxygenase-2 (COX-2) pathway is important for inflammation and mitochondrial function. However, the mechanisms by which glucocorticoid receptors (GRs) suppress COX-2 expression during PM exposure have not been elucidated yet. Hence, we examined the mechanisms underlying the dexamethasone-mediated suppression of the PM-induced COX-2/prostaglandin E2 (PGE2) pathway in A549 cells. The PM-induced increase in COX-2 protein, mRNA, and promoter activity was suppressed by glucocorticoids; this effect of glucocorticoids was antagonized by the GR antagonist RU486. COX-2 induction was correlated with the ability of PM to increase reactive oxygen species (ROS) levels. Consistent with this, antioxidant treatment significantly abolished COX-2 induction, suggesting that ROS is involved in PM-mediated COX-2 induction. We also observed a low mitochondrial membrane potential in PM-treated A549 cells, which was reversed by dexamethasone. Moreover, glucocorticoids significantly enhanced Bcl-2/GR complex formation in PM-treated A549 cells. Glucocorticoids regulate the PM-exposed induction of COX-2 expression and mitochondrial dysfunction and increase the interaction between GR and Bcl-2. These findings suggest that the COX-2/PGE2 pathway and the interaction between GR and Bcl-2 are potential key therapeutic targets for the suppression of inflammation under PM exposure.
Endurance exercise is securely linked to muscle metabolic adaptations including enhanced mitochondrial function ("Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle" [1], "Effects of exercise on mitochondrial content and function in aging human skeletal muscle" [2]). However, the link between exercise intensity and mitochondrial function in aging muscle has not been fully investigated. In order to understand how strenuous exercise affects mitochondrial function in aged mice, male C57BL/6 mice at age 24 months were randomly assigned to 3 groups: non-exercise (NE), low-intensity (LE) and high-intensity treadmill exercise group (HE). Mitochondrial complex activity and respiration were measured to evaluate mitochondrial function in mouse skeletal muscle. The data described here are related to the research article entitled "Strenuous exercise induces mitochondrial damage in skeletal muscle of old mice" [3].
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