AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism

Kahn, Barbara B.; Alquier, Thierry; Carling, David; Hardie, D. Grahame

doi:10.1016/j.cmet.2004.12.003

Cited by 2,539 publications

(2,335 citation statements)

References 77 publications

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“…Both metformin and AICAR activate the AMPactivated protein kinase (AMPK) pathway. AMPK is a serine/threonine kinase and a member of a metabolitesensing protein kinase family found in all eukaryotic cells (Kahn et al, 2005). AMPK is a cellular fuel sensor pathway sensitive to the increase of the AMP/ATP ratio.…”

Section: Introductionmentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Section: Introductionmentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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“…Once activated, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways, thus allowing for adaptive changes in growth and metabolism under low energy conditions 23. Emerging evidence indicates that AMPK can be activated by metformin in the brain, exerting a neuroprotective role in response to energy depletion through maintaining cellular energy homeostasis,24, 25, 26 promoting mitochondrial biogenesis,27 and increasing brain‐derived neurotrophic factor expression to promote neuronal survival 28.…”

Section: Introductionmentioning

confidence: 99%

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Zhu

Liu

Huang

et al. 2018

JAHA

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BackgroundSudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation.Methods and ResultsRats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation.ConclusionsTaken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.

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“…7 Newer roles for AMPK now include regulation of cell growth and proliferation, development of cell polarity, and global regulation of food intake. 7,8 Despite extensive research on the physiological role of AMPK in the metabolism of heart and skeletal muscle, [3][4][5][6]9,10 the ability of AMPK to phosphorylate myofilament proteins and, thereby, regulate the contractile apparatus in striated muscle remains unclear.…”

Section: Introductionmentioning

confidence: 99%

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Solis

Walker

2011

Protein Science

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5 0 -AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular AMP to ATP ratios rise, potentially serving as a key regulator of cellular energetics. Among the known targets of AMPK are catabolic and anabolic enzymes, but little is known about the ability of this kinase to phosphorylate myofilament proteins and thereby regulating the contractile apparatus of striated muscles. Here, we demonstrate that troponin I isoforms of cardiac (cTnI) and fast skeletal (fsTnI) muscles are readily phosphorylated by AMPK. For cTnI, two highly conserved serine residues were identified as AMPK sites using a combination of high-resolution top-down electron capture dissociation mass spectrometry, 32 P-incorporation, synthetic peptides, phospho-specific antibodies, and site-directed mutagenesis. These AMPK sites in cTnI were Ser149 adjacent to the inhibitory loop and Ser22 in the cardiac-specific N-terminal extension, at the level of cTnI peptides, the intact cTnI subunit, whole cardiac troponin complexes and skinned cardiomyocytes. Phosphorylation time-course experiments revealed that Ser149 was the preferred site, because it was phosphorylated 12-16-fold faster than Ser22 in cTnI. Ser117 in fsTnI, analogous to Ser149 in cTnI, was phosphorylated with similar kinetics as cTnI Ser149. Hence, the master energy-sensing protein AMPK emerges as a possibly important regulator of cardiac and skeletal contractility via phosphorylation of a preferred site adjacent to the inhibitory loop of the thin filament protein TnI.

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AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism

Cited by 2,539 publications

References 77 publications

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

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