Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle

Toyoda, Tarō; Hayashi, Tatsuya; Miyamoto, Licht; Yonemitsu, Shin; Nakano, Masako; Tanaka, Satsuki; Ebihara, Ken; Masuzaki, Hiroaki; Hosoda, Kiminori; Inoue, Gen; Otaka, Akira; Satô, Kenji; Fushiki, Tohru; Nakao, Kazuwa

doi:10.1152/ajpendo.00487.2003

Cited by 127 publications

(189 citation statements)

References 59 publications

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“…Furthermore, Comp C treatment abolished AICAR-induced JNK as well as caspase-3 activation, demonstrating that AICAR is acting in the sequence AMPK-JNK-caspase-3. AMPK activation through ROS has been previously demonstrated among others in endothelial cells (36), HepG2 hepatocarcinoma cells (37) and vascular smooth muscle cells (38) which may occur before or without alteration in the ATP/AMP ratio (38)(39)(40). In this respect it has been recently shown that physiologically relevant concentrations of H 2 O 2 can activate AMPK through oxidative modification of the AMPKα subunit, and it was discussed that AMPK activation, in addition to being a response to alterations in intracellular metabolic pathways, is directly influenced by cellular redox status (41).…”

Section: Discussionmentioning

confidence: 94%

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Sauer

Engel²,

Milosevic³

et al. 2011

Int J Oncol

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Abstract. The growth of cancer cells is limited by energy supply which is regulated by the energy sensor AMP-kinase (AMPK). Hence, mimicking a low energy state may inhibit cancer growth and may be exploited in anticancer therapies. In the present study, the impact of AMPK activation on cell growth and apoptosis of DU-145 prostate cancer cells was investigated. Incubation with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR) dose-dependently inhibited cell growth, activated AMPK, and inhibited mTOR. Furthermore, AICAR treatment activated c-Jun N-terminal kinase (JNK) and caspase-3, thereby initiating apoptosis. Within 60 min of treatment AICAR raised intracellular reactive oxygen species (ROS) which could be abolished in the presence of the free radical scavenger N-(2-mercaptopropionyl)glycin (NMPG), the AMPK inhibitor compound C (Comp C) and the respiratory chain complex I inhibitor rotenone, but not by the NADPH oxidase inhibitor VAS2870. Inhibition of ROS generation abolished AMPK activation by AICAR as well as JNK and caspase-3 activation. Furthermore, AMPK activation, JNK phosphorylation and cleaved caspase-3 upon AICAR treatment were abolished in the presence of Comp C. In summary, our data demonstrate that activation of AMPK by AICAR induces apoptosis of prostate cancer cells by a signaling pathway involving ROS, activation of JNK and cleaved caspase-3.

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Section: Discussionmentioning

confidence: 94%

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Sauer

Engel²,

Milosevic³

et al. 2011

Int J Oncol

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“…AMPK activity was determined as described previously, with slight modifications (40). Frozen muscles were homogenized in ice-cold lysis buffer (1:60, wt/vol) containing 20 mM HEPES (pH 7.4), 1% Triton X-100, 50 mM sodium chloride, 50 mM sodium fluoride, 5 mM sodium pyrophosphate, 2 mM dithiothreitol, 4 mg/l leupeptin, 50 mg/l trypsin inhibitor, 0.1 mM benzamidine, and 0.5 mM phenylmethylsulfonyl fluoride and then centrifuged at 14,000 g for 20 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Frozen muscles were homogenized in ice-cold lysis buffer (1:60, wt/vol) containing 20 mM HEPES (pH 7.4), 1% Triton X-100, 50 mM sodium chloride, 50 mM sodium fluoride, 5 mM sodium pyrophosphate, 2 mM dithiothreitol, 4 mg/l leupeptin, 50 mg/l trypsin inhibitor, 0.1 mM benzamidine, and 0.5 mM phenylmethylsulfonyl fluoride and then centrifuged at 14,000 g for 20 min at 4°C. The supernatants (200 g of protein) were immunoprecipitated with isoform-specific antibodies directed against the ␣1-or ␣2-subunit of AMPK (40) and protein A-Sepharose beads. The immune complex was washed extensively with 240 mM HEPES (pH 7.0) and 480 mM sodium chloride.…”

Section: Methodsmentioning

confidence: 99%

“…The immune complex was washed extensively with 240 mM HEPES (pH 7.0) and 480 mM sodium chloride. Kinase activity was determined by the phosphorylation of the SAMS peptide (40). The kinase reaction was carried out in 40 mM HEPES (pH 7.0), 0.1 mM SAMS, 0.2 mM AMP, 80 mM sodium chloride, 0.8 mM dithiothreitol, 5 mM magnesium chloride, and 0.2 mM ATP (2 Ci of [␥-32 P]ATP) for 20 min at 30°C.…”

Section: Methodsmentioning

confidence: 99%

“…AMPK, a heterotrimeric serine/ threonine protein kinase, consists of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits. Two distinct ␣-isoforms, ␣ 1 and ␣ 2 , are expressed in skeletal muscle (39), and both isoforms can be activated in response to muscle contraction (40). AMPK is allosterically activated in response to an elevation in AMP concentration or in the AMP-to-ATP ratio.…”

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confidence: 99%

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Effect of acute activation of 5′-AMP-activated protein kinase on glycogen regulation in isolated rat skeletal muscle

Miyamoto¹,

Toyoda²,

Hayashi³

et al. 2007

Journal of Applied Physiology

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5′-AMP-activated protein kinase (AMPK) has been implicated in glycogen metabolism in skeletal muscle. However, the physiological relevance of increased AMPK activity during exercise has not been fully clarified. This study was performed to determine the direct effects of acute AMPK activation on muscle glycogen regulation. For this purpose, we used an isolated rat muscle preparation and pharmacologically activated AMPK with 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Tetanic contraction in vitro markedly activated the α1- and α2-isoforms of AMPK, with a corresponding increase in the rate of 3- O-methylglucose uptake. Incubation with AICAR elicited similar enhancement of AMPK activity and 3- O-methylglucose uptake in rat epitrochlearis muscle. In contrast, whereas contraction stimulated glycogen synthase (GS), AICAR treatment decreased GS activity. Insulin-stimulated GS activity also decreased after AICAR treatment. Whereas contraction activated glycogen phosphorylase (GP), AICAR did not alter GP activity. The muscle glycogen content decreased in response to contraction but was unchanged by AICAR. Lactate release was markedly increased when muscles were stimulated with AICAR in buffer containing glucose, indicating that the glucose taken up into the muscle was catabolized via glycolysis. Our results suggest that AMPK does not mediate contraction-stimulated glycogen synthesis or glycogenolysis in skeletal muscle and also that acute AMPK activation leads to an increased glycolytic flux by antagonizing contraction-stimulated glycogen synthesis.

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AMPK α1 mediates the protective effect of adiponectin against insulin resistance in INS‐1 pancreatic β cells

Wang

Qiao

et al. 2019

Cell Biochemistry & Function

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The fat-derived protein adiponectin is known to reverse the effects of insulin resistance and to lower blood glucose levels. The AMP-activated protein kinase (AMPK) signalling pathway plays a central role in metabolism and energy homeostasis.Here, to investigate the role of AMPK in the protective effect of adiponectin against insulin resistance, we established the model of high-glucose (HG)-and high-lipid (HL)-induced insulin resistance in INS-1 pancreatic β cells. We found that 25mM of glucose and 0.4mM of palmitic acid treatment significantly increased cell apoptosis and impaired insulin secretion in INS-1 cells. However, recombinant human adiponectin dramatically reduced HG-and/or HL-induced cell apoptosis and greatly improved insulin secretion. Interestingly, adiponectin treatment also activated AMPK signalling pathway by increasing the phosphorylation of Thr172 in the AMPK α subunit; 10μM of compound C, a potent AMPK inhibitor, blocked the protective effects of adiponectin against HG/HL-induced insulin resistance. Furthermore, knockout experiments by CRISPR/Cas9 technology showed that AMPK α1, but not AMPK α2, is involved in the protective effects of adiponectin. Taken together, adiponectin reversed the effects of insulin resistance via AMPK α1, which provides a novel insight into the protective mechanism of adiponectin and may be used as a new strategy for the treatment of type 2 diabetes.Significance of the Study: Adiponectin can reverse the effects of insulin resistance and lower blood glucose levels. Here, adiponectin reduced HG/HL-induced cell apoptosis and greatly improved insulin secretion. These effects were blocked by AMPK inhibitor, compound C. Specifically, we found that AMPK α1, but not AMPK α2, mediates the protective effects of adiponectin, which provides a novel insight into the protective mechanism of adiponectin against insulin resistance.

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Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle

Cited by 127 publications

References 59 publications

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Effect of acute activation of 5′-AMP-activated protein kinase on glycogen regulation in isolated rat skeletal muscle

AMPK α1 mediates the protective effect of adiponectin against insulin resistance in INS‐1 pancreatic β cells

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