Lack of AMPKα2 enhances pyruvate dehydrogenase activity during exercise

Klein, Ditte Kjærsgaard; Pilegaard, Henriette; Treebak, Jonas T.; Jensen, Thomas E.; Viollet, Benoı̂t; Schjerling, Peter; Wojtaszewski, Jørgen F. P.

doi:10.1152/ajpendo.00382.2007

Cited by 33 publications

(44 citation statements)

References 42 publications

(46 reference statements)

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“…This is particularly surprising during exercise because skeletal muscle is performing exhaustive work and AMPK is activated under these circumstances (46,47). This finding is, however, consistent with the results of a previous study (11).…”

Section: Figuresupporting

confidence: 88%

Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

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The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism. IntroductionThe energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, ADP, and AMP are tied directly or indirectly to all energetic pathways and allosterically control numerous regulatory enzymes (2-6). Changes in adenine nucleotides typically occur such that ATP and AMP deviate in reciprocal directions, while ADP remains constant (1). Such changes are the basis for using the ratio AMP/ATP (1, 7) or the equation for cellular energy charge ([ATP + (0.5 × ADP)] / [ATP + ADP + AMP]) (8, 9) as indices of the metabolic environment. Metabolic stress is thus characterized by a rise in AMP paired with a fall in ATP levels, reflecting a decrease in energy state. A fall in energy state is of considerable importance, in part due to the regulatory role of AMP/ATP ratios on AMPK activity (10). AMPK is a metabolic switch sensitive to high AMP/ATP ratios and functions to protect the energy state by inhibiting ATP-consuming processes while stimulating ATP-producing processes. (10).In most tissues, the environment is controlled to maintain a high energy state (low AMP/ATP ratio). In skeletal muscle, for example, creatine kinase limits reductions in ATP during conditions such as exercise, when energy utilization is accelerated (11,12). The liver, in contrast, lacks creatine kinase, and exercise has been shown to markedly decrease the hepatic energy state and increase the phosphorylation of AMPK (11, 13). The regulatory...

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Section: Figuresupporting

confidence: 88%

Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

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“…This would suggest that pyruvate dehydrogenase (PDH) activity is elevated in AMPK-␣ 2 DN hearts such that PDH activity is inversely correlated with AMPK activity. This observation is consistent with previous reports (10,22) that have demonstrated that PDH activity is accelerated with exercise in the AMPK-␣ 2 KO mouse and that troglitazone activation of AMPK is associated with inhibition of PDH in muscle cells.…”

Section: Discussionsupporting

confidence: 94%

Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

Folmes¹,

Wagg²,

Shen

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Folmes CD, Wagg CS, Shen M, Clanachan AS, Tian R, Lopaschuk GD. Suppression of 5Ј-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts. Am J Physiol Heart Circ Physiol 297: H313-H321, 2009. First published May 8, 2009 doi:10.1152/ajpheart.01298.2008.-Activation of 5Ј-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) ␣2-subunit of AMPK (AMPK-␣2 DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14 C]glucose, 0.4 mM [9, 10-3 H]palmitate, and 100 U/ml insulin. AMPK-␣2 DN hearts had reduced AMPK activity at the end of reperfusion (82 Ϯ 9 vs. 141 Ϯ 7 pmol ⅐ mg Ϫ1 ⅐ min Ϫ1 ) with no changes in high-energy phosphates. Despite this, AMPK-␣2 DN hearts had improved recovery of function during reperfusion (14.9 Ϯ 0.8 vs. 9.4 Ϯ 1.4 beats ⅐ min Ϫ1 ⅐ mmHg ⅐ 10 Ϫ3 ). During reperfusion, fatty acid oxidation provided 44.0 Ϯ 2.8% of total acetyl-CoA in AMPK-␣2 DN hearts compared with 55.0 Ϯ 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 Ϯ 9.4% vs. 85.3 Ϯ 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.ischemia-reperfusion; fatty acid oxidation; glycolysis; glucose oxidation MYOCARDIAL ISCHEMIA OCCURS when the oxygen requirement of the heart exceeds the oxygen supplied via the coronary circulation and is a devastating cause of morbidity and mortality worldwide. A contributing factor to ischemia-reperfusion (I/R) injury is the type of energy substrate used by the heart during and after ischemia (34,36,48). The majority of the energy requirement of the normal well-perfused heart is met by the oxidation of fatty acids, with the remainder coming from the oxidation of carbohydrates (34,36,48). However, during ischemia, mitochondrial oxidative metabolism is suppressed,

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“…This is evidenced by the elevated cellular stress in skeletal muscle of ␣2-KD mice (i.e. AMP free and AMP free :ATP) compared with WT mice at the same absolute running speed, observations also observed in AMPK␣2 Ϫ/Ϫ and WT mice exercising at the same absolute speed (54). Furthermore, in the present study K g and R g were elevated in SVL of ␣2-KD 70% compared with WT 45% demonstrating that this muscle group, comprised primarily of fast glycolytic fibers, was recruited to a greater extent in ␣2-KD mice.…”

Section: Discussionmentioning

confidence: 56%

Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

Lee¹,

Griffee²,

Lynes³

et al. 2009

Journal of Biological Chemistry

127

151

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AMP-activated protein kinase (AMPK) has been postulated as a super-metabolic regulator, thought to exert numerous effects on skeletal muscle function, metabolism, and enzymatic signaling. Despite these assertions, little is known regarding the direct role(s) of AMPK in vivo, and results obtained in vitro or in situ are conflicting. Using a chronically catheterized mouse model (carotid artery and jugular vein), we show that AMPK regulates skeletal muscle metabolism in vivo at several levels, with the result that a deficit in AMPK activity markedly impairs exercise tolerance. Compared with wild-type littermates at the same relative exercise capacity, vascular glucose delivery and skeletal muscle glucose uptake were impaired; skeletal muscle ATP degradation was accelerated, and arterial lactate concentrations were increased in mice expressing a kinase-dead AMPK␣2 subunit (␣2-KD) in skeletal muscle. Nitric-oxide synthase (NOS) activity was significantly impaired at rest and in response to exercise in ␣2-KD mice; expression of neuronal NOS (NOS) was also reduced. Moreover, complex I and IV activities of the electron transport chain were impaired 32 ؎ 8 and 50 ؎ 7%, respectively, in skeletal muscle of ␣2-KD mice (p < 0.05 versus wild type), indicative of impaired mitochondrial function. Thus, AMPK regulates neuronal NOS expression, NOS activity, and mitochondrial function in skeletal muscle. In addition, these results clarify the role of AMPK in the control of muscle glucose uptake during exercise. Collectively, these findings demonstrate that AMPK is central to substrate metabolism in vivo, which has important implications for exercise tolerance in health and certain disease states characterized by impaired AMPK activation in skeletal muscle.The ubiquitously expressed serine/threonine AMP-activated protein kinase (AMPK) 2 is an ␣␤␥ heterotrimer postulated to play a key role in the response to energetic stress (1, 2), because of its sensitivity to increased cellular AMP levels (3). Pharmacological activation of AMPK (primarily via the AMP analogue ZMP) increases catabolic processes such as GLUT4 translocation (4, 5), glucose uptake (6, 7), long chain fatty acid (LCFA) uptake (8), and substrate oxidation (6). Concomitantly, pharmacological activation of AMPK inhibits anabolic processes, and in skeletal muscle genetic reduction of the catalytic AMPK␣2 subunit eliminates these pharmacological effects (9 -12). Thus, AMPK has been proposed to act as a metabolic master switch (2, 13, 14). Physiologically, exercise at intensities sufficient to increase free cytosolic AMP (AMP free ) levels is a potent stimulus of AMPK, preferentially activating AMPK␣2 in skeletal muscle (15)(16)(17). The metabolic profile of skeletal muscle during moderate to high intensity exercise is remarkably similar to skeletal muscle in which AMPK has been pharmacologically activated (i.e. increases in catabolic processes). This is consistent with the hypothesis that AMPK activation is required for the metabolic response to increased cellular stress....

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Lack of AMPKα2 enhances pyruvate dehydrogenase activity during exercise

Cited by 33 publications

References 42 publications

Hepatic energy state is regulated by glucagon receptor signaling in mice

Hepatic energy state is regulated by glucagon receptor signaling in mice

Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

Skeletal Muscle AMP-activated Protein Kinase Is Essential for the Metabolic Response to Exercise in Vivo

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