Kirsteen J. W. Mustard

Bio: Kirsteen J. W. Mustard is an academic researcher from University of Dundee. The author has contributed to research in topics: AMP-activated protein kinase & AMPK. The author has an hindex of 5, co-authored 5 publications receiving 323 citations.

5-Aminoimidazole-4-Carboxamide 1-β-d-Ribofuranoside Acutely Stimulates Skeletal Muscle 2-Deoxyglucose Uptake in Healthy Men

Abstract: Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 +/- 8 years, BMI 25 +/- 4 kg/m(2) [mean +/- SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R(2) = 0.88 +/- 0.09). After 3 h, 2DG uptake increased 2.1 +/- 0.8- and 4.7 +/- 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 +/- 0.6 to 10 +/- 0.6 mg x kg(-1) x min(-1) (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.

Does AMP-activated protein kinase couple inhibition of mitochondrial oxidative phosphorylation by hypoxia to pulmonary artery constriction?

Abstract: Pulmonary arteries constricts in response to hypoxia and thereby aid ventilation-perfusion matching in the lung. Although O2-sensitive mechanisms independent of mitochondria may also play a role, it is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation and that this underpins, at least in part, cell activation. Despite this consensus, the mechanism by which inhibition of mitochondrial oxidative phosphorylation couples to Ca-dependent vasoconstriction has remained elusive. To date, the field has focussed on the role of the cellular energy status (ATP), reduced redox couples and reactive oxygen species, respectively, but investigation of these hypotheses has delivered conflicting data and failed to unite the field. Recently, the AMPK cascade has come to prominence as a sensor of metabolic stress that appears to be ubiquitous throughout eukaryotes. AMPK complexes are heterotrimers comprising a catalytic subunit and regulatory and subunits, which monitor the cellular AMP/ATP ratio as an index of metabolic stress. Binding of AMP to two sites in the subunits triggers activation of the kinase via phosphorylation of the subunit at Thr-172, an effect antagonized by high concentrations of ATP. This phosphorylation is catalyzed by upstream kinases (AMPK kinases) the major form of which is a complex between the tumour suppressor kinase, LKB1, and two accessory subunits, STRAD and MO25. Given that inhibition of mitochondrial oxidative phosphorylation by hypoxia would be expected to promote a rise in the AMP/ATP ratio we considered the proposal that AMPK activation may mediate, in part, pulmonary artery constriction by hypoxia.

AMPK in Health and Disease

Abstract: The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ hete...

AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling

Abstract: The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

AMP-activated protein kinase--development of the energy sensor concept.

Abstract: The LKB1→AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory γ subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.

AMPK: a key regulator of energy balance in the single cell and the whole organism

Abstract: The AMP-activated protein kinase (AMPK) system is a key player in regulating energy balance at both the cellular and whole-body levels, placing it at centre stage in studies of obesity, diabetes and the metabolic syndrome. It is switched on in response to metabolic stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance such as leptin, adiponectin, resistin, ghrelin and cannabinoids. Once activated, it switches on catabolic pathways that generate adenosine triphosphate (ATP), while switching off ATP-consuming anabolic processes. AMPK exists as heterotrimeric complexes comprising a catalytic alpha-subunit and regulatory beta- and gamma-subunits. Binding of AMP to the gamma-subunit, which is antagonized by high ATP, causes activation of the kinase by promoting phosphorylation at threonine (Thr-172) on the alpha-subunit by the upstream kinase LKB1, allowing the system to act as a sensor of cellular energy status. In certain cells, AMPK is activated in response to elevation of cytosolic Ca2+ via phosphorylation of Thr-172 by calmodulin-dependent kinase kinase-beta (CaMKKbeta). Activation of AMPK, either in response to exercise or to pharmacological agents, has considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes and the metabolic syndrome. Two existing classes of antidiabetic drugs, that is, biguanides (for example, metformin) and the thiazolidinediones (for example, rosiglitazone), both act (at least in part) by activation of AMPK. Novel drugs activating AMPK may also have potential for the treatment of obesity.