MEF2 activation in differentiated primary human skeletal muscle cultures requires coordinated involvement of parallel pathways

Al-Khalili, Lubna; Chibalin, Alexander V.; Yu, Min; Sjödin, B.; Nylén, Carolina; Zierath, Juleen R.; Krook, Anna

doi:10.1152/ajpcell.00444.2003

Cited by 58 publications

(45 citation statements)

References 47 publications

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“…Compound C was developed as a selective inhibitor of AMPK [35] and it has been used in several studies to decipher cellular effects of AMPK [36][37][38]. Inhibition of AMPK by Compound C was evident in both hippocampal neurons and SH-SY5Y cells by its reduction of the phenformin-induced phosphorylation of ACC, a prototypical AMPK substrate commonly used as an indicator of AMPK activation [28].…”

Section: Discussionmentioning

confidence: 99%

“…To test if AMPK activation by phenformin was responsible for the dephosphorylation of Akt and GSK3, cells were treated with the selective AMPK inhibitor Compound C [35].Forthese experiments, differentiated hippocampal neurons were treated with a higher concentration of Compound C (40 mM) than the generally used 10-20 mM concentrations [35][36][37][38] because in preliminary concentration-response experiments the lower concentrations of Compound C only slightly inhibited AMPK in these cells (data not shown). Pretreatment with 40 mM Compound C reduced the phenformin-induced increase in the phosphorylation of ACC at Ser79 (Fig.…”

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Phenformin Treatment Activates Ampk and Reduces The Phosphormentioning

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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“…In skeletal muscle, activated AMPK has been demonstrated to increase GLUT4 protein level and translocation [21,49,50] via MEF2 [25,27,48] . However, the findings in adipose tissue are controversial.…”

Section: Wwwchinapharcom Feng L Et Almentioning

confidence: 99%

“…Activated AMPK stimulates GLUT4 expression [20] and basal GLUT4 translocation in both skeletal muscle and adipocytes [21][22][23][24] . Moreover, studies in cardiac and skeletal muscle have found that AMPK regulates GLUT4 in a manner dependent upon a heterodimer of MEF2A and MEF2D (myocyte enhancer factor 2) [25][26][27] , a complex that can bind to the human GLUT4 promoter [26] and thus regulate GLUT4 transcription.…”

Section: Introductionmentioning

confidence: 99%

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Song

Guan

et al. 2010

Acta Pharmacol Sin

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Aim:The roles of AMP-activated protein kinase (AMPK) and myocyte enhancer factor 2 isoforms (MEF2A, D) as mediators of the effects of ethanol on glucose transporter 4 (GLUT4) expression are unclear. We studied the effects of ethanol in adipocytes in vivo and in vitro. Methods: Thirty-six male Wistar rats were divided into three groups and given ethanol in a single daily dose of 0, 0.5, or 5 g/kg for 22 weeks. The expression of AMPK, MEF2 isoforms A and D, and GLUT4 was measured and compared in the three groups. The existence of the AMPK/MEF2/GLUT4 pathway in adipocytes and the effects of ethanol on this pathway were studied in (a) epididymal adipose tissue from six male Wistar rats subcutaneously injected with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, an AMPK activator) or with 0.9% NaCl (control); and (b) isolated rat and human adipocytes treated with or without ethanol, AICAR, and compound C (a selective AMPK inhibitor). Expression of AMPK, MEF2, and GLUT4 was measured by RT-PCR and Western blotting. Results: (1) Long-term ethanol exposure decreased activated AMPK, MEF2A, MEF2D, and GLUT4 expression in rat adipose tissue. (2) In rat and human adipocytes, AICAR-induced AMPK activation, with subsequent elevation of MEF2 and GLUT4 expression, was inhibited by compound C. (3) In vitro ethanol-treatment suppressed the AMPK/MEF2/GLUT4 pathway. Conclusion: The AMPK/MEF2/GLUT4 pathway exists in both rat and human adipocytes, and activated AMPK may positively regulate MEF2 and GLUT4 expression. Ethanol inhibition of this pathway leads to decreased GLUT4 expression, thus reducing insulin sensitivity and glucose tolerance.

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“…The GLUT4 MEF2 site (−473/−464) is required for tissue-specific and hormonal/ metabolic regulation of glucose transporters [15], providing a link between this transcription factor and GLUT4 regulation. MEF2A, MEF2C and MEF2D isoforms, but not the MEF2B isoform, are expressed in skeletal muscle and heart [16,17], and functional differences among the MEF2 isoforms exist [18]. In skeletal muscle and heart of diabetic mice, MEF2 DNA-binding activity is substantially reduced and correlated with a decrease in GLUT4 transcription rate.…”

Section: Introductionmentioning

confidence: 99%

Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1

Al-Khalili

Forsgren

Kannisto³

et al. 2005

Diabetologia

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Aims/hypothesis: The aim of this study was to determine the effect of several antidiabetic agents on insulin-stimulated glycogen synthesis, as well as on mRNA expression. Methods: Cultured primary human skeletal myotubes obtained from six healthy subjects were treated for 4 or 8 days without or with glucose (25 mmol/l), insulin (400 pmol/l), rosiglitazone (10 μmol/l), metformin (20 μmol/l) or the AMP-activated kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) (200 μmol/l). After this, insulin-stimulated glycogen synthesis was determined. mRNA levels of the glucose transporters GLUT1 and GL UT4, the peroxisomal proliferator activator receptor gamma (PPAR gamma) co-activator 1 (PGC1) and the myocytespecific enhancer factors (MEF2), MEF2A, MEF2C and MEF2D were determined using real-time PCR analysis after 8 days exposure to the various antidiabetic agents. Results: Insulin-stimulated glycogen synthesis was significantly increased in cultured human myotubes treated with insulin, rosiglitazone or metformin for 8 days, compared with non-treated cells. Furthermore, an 8-day exposure of myotubes to 25 mmol/l glucose impaired insulin-stimulated glycogen synthesis. In contrast, treatment with AICAR was without effect on insulin-mediated glycogen synthesis. Exposure to insulin, rosiglitazone or metformin increased mRNA expression of PGC1 and GLUT4, while AICAR or 25 mmol/l glucose treatment increased GLUT1 mRNA expression. Metformin also increased mRNA expression of the MEF2 isoforms. Conclusions/ interpretation: Enhanced insulin-stimulated glycogen synthesis in human skeletal muscle cell culture coincides with increased GLUT4 and PGC1 mRNA expression following treatment with various antidiabetic agents. These data show that chronic treatment of human myotubes with insulin, metformin or rosiglitazone has a direct positive effect on insulin action and mRNA expression.

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MEF2 activation in differentiated primary human skeletal muscle cultures requires coordinated involvement of parallel pathways

Cited by 58 publications

References 47 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

Long-term ethanol exposure inhibits glucose transporter 4 expression via an AMPK-dependent pathway in adipocytes

Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1

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