5-Aminoimidazole-4-carboxamide 1-β-<scp>d</scp>-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms

Longnus, Sarah L.; Wambolt, Richard B.; Parsons, Howard G.; Brownsey, Roger W.; Allard, Michael F.

doi:10.1152/ajpregu.00319.2002

Cited by 126 publications

(123 citation statements)

References 49 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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“…However, further AMPK activation through acute AICAR stimulation resulted in a decrease in glycogen levels in myotubes from control and R225W carriers. While this reduction in glycogen content following acute AICAR treatment may have resulted from the phosphorylation of glycogen synthase kinase by AMPK, it may also be the result of allosteric activation of glycogen phosphorylase by AICAR [26,46,47].…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

et al. 2010

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Aims/hypothesis AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKγ 3 subunit, PRKAG3 R225W.Methods Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [ 18 F]fluorodeoxyglucose and positron emission tomography. Results Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p < 0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p<0.05), higher basal glucose uptake (twofold, p<0.01) and higher glycogen synthesis rates (twofold, p<0.05) than control myotubes. They also had higher levels of intracellular glycogen (p<0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo. Conclusions/interpretation Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the γ 3 subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.

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“…Therefore, AICAR is not completely specific for AMPK because ZMP regulates other AMP-sensitive enzymes such as fructose-1,6-bisphosphates (32) and muscle glycogen phosphorylase (33). Given the nonspecificity of AICAR to AMPK activation and the inconsistent findings discussed above, it is important to use an animal model in which AMPK activity is eliminated to determine the role of AMPK in insulin sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

et al. 2008

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OBJECTIVE-We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.RESEARCH DESIGN AND METHODS-Muscle-specific transgenic mice expressing an inactive form of the AMPK ␣2 catalytic subunit (␣2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks.RESULTS-Compared with wild-type mice, glucose tolerance in ␣2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 U/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by ϳ50% in ␣2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the ␣2i TG mice. High-fat feeding in ␣2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle. CONCLUSIONS-The lack of skeletal muscle AMPK ␣2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK ␣2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments. Diabetes 57: 2958-2966, 2008 T he development of insulin resistance in skeletal muscle precedes the onset of type 2 diabetes by decades (1). Although the underlying mechanism is not fully understood, in recent years there has been growing interest in AMP-activated protein kinase (AMPK) as a potential target to attenuate skeletal muscle insulin resistance. As examples, two well-known therapies for type 2 diabetes, physical exercise and metformin, both activate AMPK in skeletal muscle (2). Despite this emphasis on AMPK, there is little direct evidence showing that AMPK is in fact critical in the development of skeletal muscle insulin resistance.AMPK is an energy-sensing enzyme that is activated by acute increases in the cellular AMP-to-ATP ratio. In skeletal muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress, all of which reduced cellular energy level (2). When intracellular ATP decreases, AMPK acts to switch off ATP-consuming pathways, such as glycogen, fatty acid, and protein synthesis pathways, and acts to switch on alternative pathways for ATP regeneration, such as glucose transport, glycolysis, and fatty acid oxidation. AMPK may also play a role in enhancing insulin sensitivity and/or responsiveness for glucose transport (3-6) in skeletal muscle.AMPK is a heterotrimeric serine/threonine kinase that consists of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits (7-11). In skeletal muscle, ␣2 (12,13) i...

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5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms

Cited by 126 publications

References 49 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

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

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