Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR

Sakamoto, Kei; Göransson, Olga; Hardie, D. Grahame; Alessi, Dario R.

doi:10.1152/ajpendo.00074.2004

Cited by 281 publications

(263 citation statements)

References 32 publications

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“…For example, we 28 and others 7 have shown that an increase in AMPK phosphorylation during myocardial ischemia is accompanied by a stimulation of AMPKK activity. However, we 28 and others 29 found that this activation of AMPKK is not associated with an activation of LKB1. This suggests that either calmodulindependent protein kinase kinase is involved in AMPK phosphorylation during ischemia or that there is a presence of additional, as yet unidentified, AMPKKs in the heart.…”

Section: Ampk Activation During Ischemia/reperfusioncontrasting

confidence: 59%

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk

2008

Int J Obes

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Myocardial ischemia produces an energy-deficient state in heart muscle, which if not corrected can lead to cardiomyocyte death. AMP-activated protein kinase (AMPK) is a key kinase that can increase energy production in the ischemic heart. During ischemia a rapid activation of AMPK occurs, resulting in an activation of both myocardial glucose uptake and glycolysis, as well as an increase in fatty acid oxidation. This activation of AMPK has the potential to increase energy production, thereby protecting the heart during ischemic stress. However, at clinically relevant high levels of fatty acids, ischemia-induced activation of AMPK also stimulates fatty acid oxidation during and following ischemia. This can contribute to ischemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency. As a result, AMPK activation has the potential to be either beneficial or harmful in the ischemic heart.

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Section: Ampk Activation During Ischemia/reperfusioncontrasting

confidence: 59%

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk

2008

Int J Obes

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“…The following food groups and food extracts have high AMPKactivating capacity: resveratrol (red grape skin extract) [114][115][116][117][118], nootkatone (grapefruit extract) [119], ajoene (garlic extract) [120], BDIM (cruciferous vegetable extract) [19,121], and many others [122]. Medicines activate AMPK including Asa [16], Met [35], phenformin [123,124], rosiglitazone, and phenobarbital [125,126], and there may be others.…”

Section: Discussionmentioning

confidence: 99%

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Bolnick

Abdulhasan

Kilburn

et al. 2016

J Assist Reprod Genet

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Purpose The purpose of the present study is to test whether metformin, aspirin, or diet supplement (DS) BioResponse-3, 3′-Diindolylmethane (BR-DIM) can induce AMP-activated protein kinase (AMPK)-dependent potency loss in cultured embryos and whether metformin (Met) + Aspirin (Asa) or BR-DIM causes an AMPK-dependent decrease in embryonic development. Methods The methods used were as follows: culture post-thaw mouse zygotes to the two-cell embryo stage and test effects after 1-h AMPK agonists' (e.g., Met, Asa, BR-DIM, control hyperosmotic stress) exposure on AMPK-dependent loss of Oct4 and/or Rex1 nuclear potency factors, confirm AMPK dependence by reversing potency loss in two-cell-stage embryos with AMPK inhibitor compound C (CC), test whether Met + Asa (i.e., co-added) or DS BR-DIM decreases development of two-cell to blastocyst stage in an AMPK-dependent (CCsensitive) manner, and evaluate the level of Rex1 and Oct4 nuclear fluorescence in two-cell-stage embryos and rate of two-cell-stage embryo development to blastocysts. Result(s) Met, Asa, BR-DIM, or hyperosmotic sorbitol stress induces rapid~50-85 % Rex1 and/or Oct4 protein loss in twocell embryos. This loss is~60-90 % reversible by co-culture with AMPK inhibitor CC. Embryo development from twocell to blastocyst stage is decreased in culture with either Met + Asa or BR-DIM, and this is either >90 or~60 % reversible with CC, respectively. Conclusion These experimental designs here showed that Met-, Asa-, BR-DIM-, or sorbitol stress-induced rapid potency loss in two-cell embryos is AMPK dependent as suggested by inhibition of Rex1 and/or Oct4 protein loss with an AMPK inhibitor. The DS BR-DIM or fertility drugs (e.g., Met + Asa)Capsule Drugs metformin and aspirin and diet supplement BR-DIM cause AMPK-dependent potency loss and decrease embryonic development from two-cell to blastocyst stage. Reprod Genet (2016) 33:1027-1039 DOI 10.1007 that are used to enhance maternal metabolism to support fertility can also chronically slow embryo growth and block development in an AMPK-dependent manner.

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“…In order to investigate its physiological effects, AMPK is often experimentally activated by either of two agents, phenformin or AICAR. These two drugs activate AMPK by different mechanisms, with AICAR structurally mimicking the endogenous activator AMP, while several different mechanisms involving activation of an AMPK-phosphorylating kinase have been proposed for the effect of phenformin and its analog metformin [43][44][45][46][47][48]. In non-proliferating differentiated hippocampal neurons and in proliferating neuroblastoma SH-SY5Y cells, the present study found that both phenformin and AICAR not only activated AMPK, but also greatly reduced the phosphorylation of Akt on its regulatory Ser/Thr sites.…”

Section: Discussionmentioning

confidence: 99%

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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Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR

Cited by 281 publications

References 32 publications

AMP-activated protein kinase control of energy metabolism in the ischemic heart

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

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

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