Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia

Marsin, Anne Sophie; Bertrand, Luc; Rider, Mark H.; Deprez, Johan; Beauloye, Christophe; Vincent, M F; Berghe, Georges; Carling, David; Hue, Louis

doi:10.1016/s0960-9822(00)00742-9

Cited by 728 publications

(582 citation statements)

References 39 publications

Supporting

Mentioning

542

Contrasting

Unclassified

Order By: Relevance

“…Experimentally, and potentially clinically, this may be mediated by administration of metformin, which diminishes diabetic cardiomyopathy in a chronic type 1 diabetic model via activation of AMP kinase 43. A potential, and unexamined, benefit of sustained activation of AMP kinase may be by the phosphorylation and stabilization of PFK‐2 44. Alternatively, targeting the concerted actions of PFK‐2 and PFK‐1 more specifically may be a way to potently reverse diabetic metabolic changes.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Humphries

Matsuzaki

Vadvalkar

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundThe healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK‐2) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK‐2 content, activity, and cardiac metabolism.Methods and ResultsStreptozotocin‐induced diabetes mellitus, high‐fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK‐2 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK‐2 degradation. Both type 1 diabetes mellitus and a high‐fat diet induced a significant decrease in cardiac PFK‐2 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK‐2, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK‐2 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse‐1, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK‐2 is rapidly degraded via both proteasomal‐ and chaperone‐mediated autophagy.ConclusionsThe loss of PFK‐2 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.

show abstract

Section: Discussionmentioning

confidence: 99%

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Humphries

Matsuzaki

Vadvalkar

et al. 2017

JAHA

View full text Add to dashboard Cite

show abstract

“…Deprivation of oxygen (hypoxia) is another stress that can limit catabolism, thus causing increases in AMP: ATP and AMPK activation. This occurs, for example, in cardiac muscle in response to ischaemia, an interruption in the blood supply (21)(22)(23) . Similar to what has just been described for hypoglycaemia, in most cells the oxygen tension has to drop to pathologically low levels (such as occurs during ischaemia) before AMPK is activated.…”

Section: Activation Of Mammalian Amp-activated Protein Kinase By Metamentioning

confidence: 99%

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Hardie

2010

Proc. Nutr. Soc.

119

View full text Add to dashboard Cite

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP :ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-ofrapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished. Muscle: Exercise: Type 2 diabetes: NutraceuticalsAnimal cells take up fuel molecules such as glucose or fatty acids, and oxidise them to CO 2 via the process of catabolism. Much of the energy released during this process is used to convert ADP to ATP, which can be likened to the chemicals in a rechargeable battery. Extending this analogy, catabolism charges up the battery by converting ADP to ATP, whereas most other cellular activities (e.g. growth, division, secretion and movement) require energy and are driven by the conversion of ATP back to ADP, thus draining the battery. Just as machines that utilise rechargeable batteries (such as laptop computers or electric cars) require systems to monitor the state of the battery, cells require systems to monitor their ATP : ADP ratio and match the rates of uptake and consumption of carbon nutrients to the rate of ATP utilisation. The topic of this review is the AMP-activated protein kinase (AMPK), which is the major system responsible for achieving this task in eukaryotes. Researchers who wish to understand disorders of energy balance, such as obesity and type-2 diabetes, have been particularly interested in the system. Protein kinases, including AMPK, are signalling enzymes that modify the function of target proteins by transferring phosphate groups from ATP to side chains of specific amino acids, usually serine o...

show abstract

“…We first demonstrated that AMPK activation occurs during myocardial ischemia, 2,3 a finding now reproduced by numerous laboratories. 4,[7][8][9][10][11]23,24 This activation of AMPK presumably occurs as an approach to restore myocyte ATP levels, primarily turning on ATP generating pathways. It is now clear that AMPK activation can increase both glucose and fatty acid metabolism in the ischemic heart.…”

Section: Ampk Activation During Ischemia/reperfusionmentioning

confidence: 99%

“…8 AMPK also phosphorylates and activates phosphofructokinase 2, 24 which produces fructose 2,6-bisphosphate, a potent stimulator of glycolysis. As AMPK has an important role in promoting glucose uptake and glycolysis, 24,37,38 the activation of AMPK during ischemia may benefit the heart by increasing glucose utilization (and subsequently anaerobic ATP synthesis).…”

Section: Ampk Activation During Ischemia/reperfusionmentioning

confidence: 99%

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

Lopaschuk

2008

Int J Obes

View full text Add to dashboard Cite

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.

show abstract

Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia

Abstract: AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia.

Cited by 728 publications

References 39 publications

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

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

Contact Info

Product

Resources

About