Article

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

College of Life Sciences, University of Dundee, Dundee, UK.
Proceedings of The Nutrition Society (Impact Factor: 5.27). 11/2010; 70(1):92-9. DOI: 10.1017/S0029665110003915
Source: PubMed

ABSTRACT

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-of-rapamycin 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.

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Available from: David G Hardie, Feb 24, 2014
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    • "AMPK is considered a master switch in muscle metabolism and key in the regulation of transport of fuel into the mitochondria for oxidation. During exercise increased AMPK activity stimulates FA utilization (Fentz et al., 2015) and inhibits other energy-consuming processes (Jorgensen et al., 2004;Jensen et al., 2009;Richter & Ruderman, 2009;Hardie, 2011). Furthermore, AMPK may partly favor FA oxidation through inhibition of Acetyl-CoA carboxylase 2 (ACC2) (Stephens et al., 2002) although this may not be a limiting factor (Dzamko et al., 2008). "
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    ABSTRACT: Age and inactivity have been associated with intramuscular triglyceride (IMTG) accumulation. Here, we attempt to disentangle these factors by studying the effect of 2 weeks’ unilateral leg immobilization on substrate utilization across the legs during moderate intensity exercise in young (n = 17; 23 ± 1 years) and older (n = 15; 68 ± 1 years) men, while the contralateral leg served as control. After immobilization, the participants performed two-legged isolated knee-extensor exercise at 20 ± 1 Watt (∼50% Wattmax) for 45 min with catheters inserted in the brachial artery and both femoral veins. Biopsy samples obtained from vastus lateralis muscles of both legs before and after exercise were used for analysis of substrates, protein content and enzyme activities. During exercise, leg substrate utilization (RQ) did not differ between groups or legs. Leg fatty acid (FA) uptake was greater in older than in young men, and while young men demonstrated net leg glycerol release during exercise, older men showed net glycerol uptake. At baseline, IMTG, muscle pyruvate dehydrogenase complex activity, protein content of adipose triglyceride lipase (ATGL), acetyl-CoA carboxylase 2, AMP-activated protein kinase (AMPK)γ3 were higher in young than in older men. Furthermore, ATGL, plasma membrane-associated FA binding protein, and AMPKγ3 subunit protein content were lower and IMTG being higher in the immobilized than the contralateral leg in young and older men. Thus, immobilization and age did not affect substrate choice (RQ) during moderate exercise, but the whole-leg and molecular differences in FA mobilization could explain the age and immobilization induced IMTG accumulation. This article is protected by copyright. All rights reserved
    Full-text · Article · Jan 2016 · The Journal of Physiology
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    • "The signaling proteins that regulate exercise-and contraction-stimulated glucose uptake are still not clearly understood, and there is considerable evidence that redundant signaling mechanisms may control this important physiological process (Rockl et al. 2008). AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, has been proposed to be the central node regulating glucose transport in response to insulin-independent stimuli such as exercise, muscle contraction, hypoxia, metformin, and the AMPK activator AICAR (Merrill et al. 1997; Mu et al. 2001; Sajan et al. 2010; Hardie 2011; Richter and Hargreaves 2013). A number of studies using different animal models have convincingly demonstrated that AMPK is necessary for AICAR-and metformin-stimulated glucose transport (Zhou et al. 2001; Fryer et al. 2002; Sajan et al. 2010). "
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    ABSTRACT: Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζ(WT)), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζ(T410A)). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζ(WT), and PKC-ζ(T410A) tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζ(T410A) tibialis anterior muscles compared to WT or PKC-ζ(WT) tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λζ activity is not necessary for contraction-stimulated glucose uptake.
    Full-text · Article · Nov 2015
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    • "VWR decreased liver Scd1 expression in HOM wheel-runners compared to sedentary HOM controls (Figure 7H). The central melanocortin system regulates leptininduced skeletal muscle AMPK activation and GLUT4 translocation [54] [55], resulting in decreased skeletal muscle glucose uptake during MC4R deficiency [56]. Because impaired substrate utilization can decrease exercise capacity, we measured protein levels of GLUT4 and HXK2, important regulators of increased muscle glucose utilization during exercise [57], in triceps muscle after 5 wk of VWR. "
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    ABSTRACT: Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r (K314X) (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB (Mc4r) mice, wild-type mice body weight-matched to loxTB (Mc4r) mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.
    Full-text · Article · Jul 2015 · Molecular Metabolism
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