AICAR stimulation metabolome widely mimics electrical contraction in isolated rat epitrochlearis muscle

Miyamoto, Licht; Egawa, Tatsuro; Oshima, Rieko; Kurogi, Eriko; Tomida, Yosuke; Tsuchiya, Koichiro; Hayashi, Tatsuya

doi:10.1152/ajpcell.00162.2013

Cited by 16 publications

(18 citation statements)

References 57 publications

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“…In the present study, 4-h exposure to 15 % cyclic uniaxial stretch at the frequency of 1 Hz significantly increased the phosphorylation of p70S6K in myotubes, suggesting that mechanical stretch activates the initiation of protein translation. In contrast, mechanical stimulus-induced activation of AMPK has also been demonstrated in skeletal muscle cell in vivo [38], ex vivo [39,40], and in vitro [41]. In the present study, phosphorylation of AMPK at T172 of the catalytic a subunit was significantly higher in stretched cells, suggesting that mechanical stretch activated AMPK.…”

Section: Discussioncontrasting

confidence: 57%

Mechanical stretch activates mammalian target of rapamycin and AMP-activated protein kinase pathways in skeletal muscle cells

2015

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Cellular protein synthesis is believed to be antagonistically regulated by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways. In the present study, we examined the relationship between mTOR/p70 S6 kinase (p70S6K) and AMPK in response to mechanical stretch. C2C12 myoblasts were grown on a silicone elastomer chamber to confluence and further cultured in differentiation medium for 4 days to form multinucleated myotubes. Cells were subjected to 15% cyclic uniaxial stretch for 4 h at a frequency of 1 Hz. Phosphorylation of p70S6K at threonine 389 and AMPK at threonine 172 of the catalytic α subunit were concomitantly increased by mechanical stretch. Stimulation of the mTOR pathway by adding leucine and insulin increased the phosphorylation of p70S6K without inactivation of AMPK. In contrast, addition of compound C, a pharmacological inhibitor of AMPK, increased the phosphorylation of p70S6K in stretched cells. Activation of AMPK by the addition of 5-amino-4-imidazolecarboxamide ribonucleoside reduced the phosphorylation of p70S6K in response to mechanical stretch. In conclusion, crosstalk between mTOR and AMPK signaling was not tightly regulated in response to physiological stimuli, such as mechanical stress and/or nutrients. However, pharmacological modulation of AMPK influenced the mTOR/p70S6K signaling pathway.

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Section: Discussioncontrasting

confidence: 57%

Mechanical stretch activates mammalian target of rapamycin and AMP-activated protein kinase pathways in skeletal muscle cells

2015

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“…This activates AMPK allosterically and decreases the ability of upstream phosphatases to dephosphorylate Thr 172 , which further increases AMPK phosphorylation and activity (21). Like exercise, AICAR increases AMPK activity in skeletal muscle (22), which partly mimics the metabolic changes observed during muscle contraction (23).…”

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confidence: 99%

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

et al. 2014

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An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr 649 and Ser 711 in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.The effect of insulin on skeletal muscle glucose uptake is increased in the period after a single bout of exercise. This phenomenon is observed in muscle from both humans and rodents (1-6) and may persist for up to 48 h after exercise, depending on carbohydrate availability (7-9). Improved muscle insulin sensitivity postexercise is mediated by one or several local contraction-induced mechanisms (10) involving both enhanced transport and intracellular processing of glucose. This period is characterized by increased GLUT4 protein abundance at the plasma membrane and enhanced glycogen synthase activity (11,12). These changes occur independent of global protein synthesis (13), including both total GLUT4 and glycogen synthase protein content (4,11), and are independent of changes in proximal insulin signaling, including Akt activation (3,4,(13)(14)(15)(16)(17).AMPK is a heterotrimeric complex consisting of catalytic (a1/a2) and regulatory subunits (b1/b2 and g1/g2/g3). Of the 12 heterotrimeric combinations, only 3 and 5 combinations have been found in the skeletal muscle of human and mouse, respectively (18,19). AMPK is activated in response to various stimuli that increase cellular energy stress (e.g., metformin, hypoxia, hyperosmolarity, muscle contraction, and exercise) (20). With energy stress, intracellular concentrations of AMP and ADP accumulate. This activates AMPK allosterically and decreases the ability of upstream phosphatases to dephosphorylate Thr 172 , which further increases AMPK phosphorylation and activity (21). Like exercise, AICAR increases AMPK activity in skeletal muscle (22), which partly mimics the metabolic changes observed during muscle contraction (...

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“…[47][48][49][50][51] AMPK plays important roles in improving exercise tolerance as well as acute metabolic responses in terms of skeletal muscle contraction. 28,52) They all suggest the importance of nitrate-nitrite-derived NO production in the amelioration of muscle energetics. Our observations suggest the significance of nitrite-stimulated AMPK in the nitrateevoked improvement of exercise performances.…”

Section: Discussionmentioning

confidence: 98%

“…A variety of metabolic stresses and hormonal stimulations such as physical exercise, leptin and adiponectin have been reported to activate AMPK, which leads to lots of metabolic responses metabolome-widely including glucose uptake, fatty acid oxidation, and insulin sensitization etc. [28][29][30][31][32][33][34][35][36] In addition, AMPK plays significant roles in a variety of homeostatic regulations in the tissues throughout our bodies. In endothelial cells, AMPK is a potent stimulator of vasodilation.…”

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confidence: 99%

Nitrite Activates 5′AMP-Activated Protein Kinase-Endothelial Nitric Oxide Synthase Pathway in Human Glomerular Endothelial Cells

Miyamoto

Yamane

Tomida

et al. 2017

Biological & Pharmaceutical Bulletin

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Recent studies have shown that orally supplied nitrates, which substantially exist in our daily diets, are reduced into nitrites and become significant sources of nitric oxide (NO) especially in hypoxic tissues. However, physiological significance of nitrites in normal tissues has not been elucidated though our serum concentrations of nitrites reach as high as micromolar levels. We investigated effects of nitrite on endothelial NO synthase (eNOS) using human glomerular endothelial cells to reveal potential glomerular-protective actions of nitrites with its underlying molecular mechanism. Here we demonstrate that nitrite stimulation evokes eNOS activation which is dependent on 5′AMP-activated protein kinase (AMPK) activation in accordance with ATP reduction. Thus, nitrites should facilitate AMPK-eNOS pathway in an energy level-dependent manner in endothelial cells. The activation of AMPK-eNOS signals is suggested to be involved in vascular and renal protective effects of nitrites and nitrates. Nitrites may harbor beneficial effects on metabolic regulations as AMPK activators.Key words nitrite; 5′AMP-activated protein kinase; endothelial nitric oxide synthase; human glomerular endothelial cell (HGEC); nitrate Nitric oxide (NO) is an important signaling molecule involved in many physiological processes. Above all, NO is a dominant vasodilator released from endothelial cells and identified as the nature of endothelium-derived relaxant factor so called, which regulates blood pressures.1) In addition, NO prevents endothelial apoptosis, platelet aggregation and has tissue-protective actions against such proinflammatory and proatherogenic stimulations.2-4) NO is produced from arginine by three distinct isoforms of nitric oxide synthase (NOS). In uninjured endothelial cells, endothelial NOS (eNOS) dominantly catabolizes the NO production. Therefore, appropriate regulation of eNOS activity is quite important to keep vessels and tissues in good conditions. Disruption of endothelial NO synthesis has been reported in such diseases as hypertension, diabetes and hyperlipidemia in accordance. 5-8)The half-life of NO in blood is just in seconds and metabolized into inert nitrate via nitrite. In addition, our daily diets, especially vegetables, ordinarily contain considerable amounts of nitrate and nitrite, and significant concentrations of them distributes throughout our bodies. An analysis using capillary electrophoresis revealed the concentrations of nitrite and nitrate in normal human serum are around 6.6 and 34 µM, respectively. 9)Exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate it enough for normal biological functions. Recent studies have established the notion of nitrate-nitrite-NO pathway (reviewed in 10,11) ). In brief, dietary and salivary glands-secreted nitrate is reduced into nitrite by bacteria in oral cavity. The nitrite is converted into nitrogen oxides including NO in the stomach or other acidic environments. The resultant nitrate in the plasma is taken up and re-secr...

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AICAR stimulation metabolome widely mimics electrical contraction in isolated rat epitrochlearis muscle

Cited by 16 publications

References 57 publications

Mechanical stretch activates mammalian target of rapamycin and AMP-activated protein kinase pathways in skeletal muscle cells

Mechanical stretch activates mammalian target of rapamycin and AMP-activated protein kinase pathways in skeletal muscle cells

Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner

Nitrite Activates 5′AMP-Activated Protein Kinase-Endothelial Nitric Oxide Synthase Pathway in Human Glomerular Endothelial Cells

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