Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase

Hutber, C. A.; Hardie, D. Grahame; Winder, W. W.

doi:10.1152/ajpendo.1997.272.2.e262

Cited by 165 publications

(183 citation statements)

References 18 publications

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“…1A). These results are consistent with several studies that have reported that phosphorylation of ACC is a sensitive marker of AMPK activity, often more sensitive even than increased levels of phosphoThr172-AMPK [29][30][31][32][33], and verify that phenformin treatment activated AMPK in differentiated hippocampal neurons.…”

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphorsupporting

confidence: 93%

“…Treatment with 10 mM phenformin caused a rapid, time-dependent increase in the phosphorylation of Ser79-ACC (Fig. 1A), a well-characterized substrate of AMPK [28] that is widely used as a detector of AMPK activation [29][30][31][32][33]. The phenformin-induced increase in phospho-Ser79-ACC was evident within 10 min of treatment and was maintained for 120 min.…”

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

confidence: 96%

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AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

122

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AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimida-zole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serinephosphorylation of its substrates, glycogen synthase kinase-3a/b (GSK3a/b). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factorinduced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.

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Section: Phenformin Treatment Activates Ampk and Reduces The Phosphorsupporting

confidence: 93%

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

confidence: 96%

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

King

Lee

Jope

2006

Biochemical Pharmacology

122

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“…In myocytes, AMPK is activated by increases in the AMP:ATP ratio, which is brought about by hypoxia/anoxia (8 -10), vigorous exercise and muscle contraction (11)(12)(13)(14) or pressure-overload hypertrophy (15). Under these conditions, AMPK is activated by a conformational change after binding AMP (16,17), and by phosphorylation by its upstream kinase AMPK kinase (AMPKK) (17)(18)(19).…”

mentioning

confidence: 99%

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Nagata¹,

Mogi

Walsh

2003

Journal of Biological Chemistry

322

338

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AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that is regulated by hypoxia and other cellular stresses that result in diminished cellular ATP levels. Here, we investigated whether AMPK signaling in endothelial cells has a role in regulating angiogenesis. Hypoxia induced the activating phosphorylation of AMPK in human umbilical vein endothelial cells (HUVECs), and AMPK activation was required for the maintenance of pro-angiogenic Akt signaling under these conditions. Suppression of AMPK signaling inhibited both HUVEC migration to VEGF and in vitro differentiation into tube-like structures in hypoxic, but not normoxic cultures. Dominant-negative AMPK also inhibited in vivo angiogenesis in Matrigel plugs that were implanted subcutaneously in mice. These data identify AMPK signaling as a new regulator of angiogenesis that is specifically required for endothelial cell migration and differentiation under conditions of hypoxia. As such, endothelial AMPK signaling may be a critical determinant of blood vessel recruitment to tissues that are subjected to ischemic stress.Angiogenesis is central feature of normal embryonic and post-natal development, and this process plays a critical role in the neovascularization that is associated with tumor growth and occlusive vascular diseases (1-3). A large body of evidence has shown that vascular angiogenic growth factors promote angiogenesis through activation of MAP kinase (4) and phosphatidylinositol 3-kinase (PI3K)-Akt/PKB (5) intracellular signaling pathways. However, the signaling molecules involved in angiogenic cellular responses under conditions of hypoxic stress is incompletely understood.AMP-activated protein kinase (AMPK) 1 is a metabolite-sensing protein kinase that shares amino acid sequence homology with yeast SNF1 (6, 7). In myocytes, AMPK is activated by increases in the AMP:ATP ratio, which is brought about by hypoxia/anoxia (8 -10), vigorous exercise and muscle contraction (11-14) or pressure-overload hypertrophy (15). Under these conditions, AMPK is activated by a conformational change after binding AMP (16,17), and by phosphorylation by its upstream kinase AMPK kinase (AMPKK) (17-19). Upon activation, AMPK phosphorylates and down-regulates several anabolic enzymes including 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (16,20), acetyl-CoA carboxylase (ACC) (16, 21), sn-glycerol-3-phosphate acetyltransferase (22, 23), and glycogen synthase (24); thereby diminishing metabolite flux through synthetic pathways that consume ATP. AMPK activation also accelerates ␤-oxidation of fatty acid, which promotes ATP production (25, 26).Endothelial nitric-oxide synthase (eNOS) residue 1177 (in human) is a substrate for both Akt (27, 28) and AMPK (29). Phosphorylation of eNOS at this residue leads to enzyme activation and nitric oxide (NO) production. AMPK is reported to phosphorylate eNOS in cardiac myocytes under hypoxic conditions (29), but it is not clear whether NO production by endothelial cells is regulated by this reaction. Recently, AMPK ...

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“…Upon stimulation, AMPK switches off ATPconsuming anabolic pathways and activates ATPproducing catabolic processes. In skeletal muscle, AMPK is activated in response to metabolic stresses such as hypoxia, hyperosmolarity, mitochondrial uncoupling, contractile activity, and exercise in vivo (2)(3)(4)(5)(6)(7)(8). The levels of AMP, ATP, and creatin phosphate (CrP) seem to be the major determinants for the activation of AMPK, by direct allosteric regulation and by phosphorylation induced by upstream kinases (1,9).…”

mentioning

confidence: 99%

Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle

et al. 2002

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1 5-AMP-activated protein kinase (AMPK) functions as a metabolic switch in mammalian cells and can be artificially activated by 5-aminoimidazole-4-carboxamide (AICA)-riboside. AMPK activation during muscle contraction is dependent on muscle glycogen concentrations, but whether glycogen also modifies the activation of AMPK and its possible downstream effectors (glycogen synthase and glucose transport) by AICA-riboside in resting muscle is not known. Thus, we have altered muscle glycogen levels in rats by a combination of swimming exercise and diet and investigated the effects of AICA-riboside in the perfused rat hindlimb muscle. Two groups of rats, one with super-compensated muscle glycogen content (ϳ200 -300% of normal; high glycogen [HG]) and one with moderately lowered muscle glycogen content (ϳ80% of normal; low glycogen [LG]), were generated. In both groups, the degree of activation of the ␣2 isoform of AMPK by AICA-riboside depended on muscle type (white gastrocnemius Ͼ Ͼ red gastrocnemius > soleus). Basal and AICA-riboside-induced ␣2-AMPK activity were markedly lowered in the HG group (ϳ50%) compared with the LG group. Muscle 2-deoxyglucose uptake was also increased and glycogen synthase activity decreased by AICA-riboside. Especially in white gastrocnemius, these effects, as well as the absolute activity levels of AMPK-␣2, were markedly reduced in the HG group compared with the LG group. The inactivation of glycogen synthase by AICA-riboside was accompanied by decreased gel mobility and was eliminated by protein phosphatase treatment. We conclude that acute AICA-riboside treatment leads to phosphorylation and deactivation of glycogen synthase in skeletal muscle. Although the data do not exclude a role of other kinases/phosphatases, they suggest that glycogen synthase may be a target for AMPK in vivo. Both basal and AICA-riboside-induced AMPK-␣2 and glycogen synthase activities, as well as glucose transport, are depressed when the glycogen stores are plentiful. Because the glycogen level did not affect adenine nucleotide concentrations, our data suggest that glycogen may directly affect the activation state of AMPK in skeletal muscle. Diabetes 51:284 -292, 2002

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Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase

Cited by 165 publications

References 18 publications

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle

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