Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction

Jensen, Thomas E.; Rose, Adam J.; Jørgensen, Sebastian Beck; Brandt, Nina; Schjerling, Peter; Wojtaszewski, Jørgen F. P.

doi:10.1152/ajpendo.00456.2006

Cited by 183 publications

(206 citation statements)

References 62 publications

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“…These findings are consistent with previous reports in ␣2 KO (40), ␥3 KO (41), and KD mice (31). Taken together these data suggest one of three possibilities for the maintenance of contraction-stimulated glucose uptake and fatty acid oxidation: 1) ␤1 containing heterotrimers are capable of compensating; 2) AMPK independent pathways activated by muscle contraction such as calcium/calmodulin-dependent kinase II may be important (55,56); or 3) because contraction-stimulated glucose uptake is reduced in muscle-specific LKB1 null mice (57) these data may indicate that AMPK-related kinases may be important for controlling contraction-stimulated glucose uptake and fatty acid oxidation. Future studies in mice with muscle-specific deletion of both ␤1 and ␤2 should help determine more directly the importance of AMPK in regulating metabolism during muscle contractions.…”

Section: Discussionsupporting

confidence: 92%

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Steinberg

O’Neill

Dzamko

et al. 2010

Journal of Biological Chemistry

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146

139

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AMP-activated protein kinase (AMPK) ␤ subunits (␤1 and ␤2) provide scaffolds for binding ␣ and ␥ subunits and contain a carbohydrate-binding module important for regulating enzyme activity. We generated C57Bl/6 mice with germline deletion of AMPK ␤2 (␤2 KO) and examined AMPK expression and activity, exercise capacity, metabolic control during muscle contractions, aminoimidazole carboxamide ribonucleotide (AICAR) sensitivity, and susceptibility to obesity-induced insulin resistance. We find that ␤2 KO mice are viable and breed normally. ␤2 KO mice had a reduction in skeletal muscle AMPK ␣1 and ␣2 expression despite up-regulation of the ␤1 isoform. Heart AMPK ␣2 expression was also reduced but this did not affect resting AMPK ␣1 or ␣2 activities. AMPK ␣1 and ␣2 activities were not changed in liver, fat, or hypothalamus. AICAR-stimulated glucose uptake but not fatty acid oxidation was impaired in ␤2 KO mice. During treadmill running ␤2 KO mice had reduced maximal and endurance exercise capacity, which was associated with lower muscle and heart AMPK activity and reduced levels of muscle and liver glycogen. Reductions in exercise capacity of ␤2 KO mice were not due to lower muscle mitochondrial content or defects in contraction-stimulated glucose uptake or fatty acid oxidation. When challenged with a high-fat diet ␤2 KO mice gained more weight and were more susceptible to the development of hyperinsulinemia and glucose intolerance. In summary these data show that deletion of AMPK ␤2 reduces AMPK activity in skeletal muscle resulting in impaired exercise capacity and the worsening of diet-induced obesity and glucose intolerance.The AMP-activated protein kinase (AMPK) 5 is an evolutionary conserved serine/threonine protein kinase that functions as a metabolic regulatory enzyme at both the intracellular and whole body level (1, 2). As a metabolic stress-sensing enzyme, AMPK is activated through phosphorylation of Thr 172 in the ␣-catalytic subunit by upstream kinases, liver kinase B1 (LKB1) and calcium/calmodulin-dependent kinase kinase in response to physiological processes that consume ATP (exercise) or inhibit ATP production (ischemia or hypoxia) (3). Following activation, AMPK acutely regulates lipid, protein, and carbohydrate metabolism through phosphorylation induced changes that alter enzyme activities by switching off ATP consuming anabolic pathways and switching on ATP generating catabolic pathways (4). In addition to these acute effects, AMPK regulates transcription factors to influence gene expression (4). Modulation of AMPK activity by hormones and cytokines adds a complex layer of regulation allowing energy supply and demand within a cell to be integrated with the energy requirements of the whole organism (5).AMPK functions as an ␣␤␥ heterotrimer where the C terminus of the ␤ isoforms (␤1 and ␤2) contains the subunit-binding sequence that is essential for binding the ␥ and ␣ subunits (6, 7). In addition to their structural role in maintaining the AMPK heterotrimer, AMPK ␤ subunits contain an evolutionary ...

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Section: Discussionsupporting

confidence: 92%

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Steinberg

O’Neill

Dzamko

et al. 2010

Journal of Biological Chemistry

Self Cite

146

139

View full text Add to dashboard Cite

show abstract

“…Thus our finding that ablation of LKB1 did not prevent the action of metformin is surprising. However, there are other upstream AMPK kinases, such as the Ca 2ϩ -calmodulin protein kinase (58). Moreover, it is known that elevation in AMP concentrations alone can activate and phosphorylate AMPK, even without alterations in the upstream kinases, as AMP binding to AMPK makes it both a better phosphorylation substrate and a poorer protein phosphatase substrate (59).…”

Section: Discussionmentioning

confidence: 99%

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Ouyang

Parakhia

Ochs

2011

Journal of Biological Chemistry

206

181

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The mechanism for how metformin activates AMPK (AMPactivated kinase) was investigated in isolated skeletal muscle L6 cells. A widely held notion is that inhibition of the mitochondrial respiratory chain is central to the mechanism. We also considered other proposals for metformin action. As metabolic pathway markers, we focused on glucose transport and fatty acid oxidation. We also confirmed metformin actions on other metabolic processes in L6 cells. Metformin stimulated both glucose transport and fatty acid oxidation. The mitochondrial Complex I inhibitor rotenone also stimulated glucose transport but it inhibited fatty acid oxidation, independently of metformin. The peroxynitrite generator 3-morpholinosydnonimine stimulated glucose transport, but inhibited fatty acid oxidation. Addition of the nitric oxide precursor arginine to cells did not affect glucose transport. These studies differentiate metformin from inhibition of mitochondrial respiration and from active nitrogen species. Knockdown of adenylate kinase also failed to affect metformin stimulation of glucose transport. Hence, any means of increase in ADP appears not to be involved in the metformin mechanism. Knockdown of LKB1, an upstream kinase and AMPK activator, did not affect metformin action. Having ruled out existing proposals, we suggest a new one: metformin might increase AMP through inhibition of AMP deaminase (AMPD). We found that metformin inhibited purified AMP deaminase activity. Furthermore, a known inhibitor of AMPD stimulated glucose uptake and fatty acid oxidation. Both metformin and the AMPD inhibitor suppressed ammonia accumulation by the cells. Knockdown of AMPD obviated metformin stimulation of glucose transport. We conclude that AMPD inhibition is the mechanism of metformin action.

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“…By contrast, a1 activity was reduced but not eliminated in both muscles, and in cardiac muscle was still stimulated by ischaemia [23,24]. Whether CaMKKs are responsible for the residual, LKB1-independent activity of a1 complexes is not completely resolved, although there is evidence using pharmacological inhibitors that CaMKKs could be responsible for activation of AMPK in skeletal muscle during electrical stimulation of low intensity or short duration [25,26]. The LKB1 pathway may become more significant after longer and more intense contractions, when ATP depletion is likely to be more marked.…”

Section: Mammalian Ampk -Regulation By Amp/atp and Upstream Kinasesmentioning

confidence: 99%

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

2007

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Obesity, type 2 diabetes and the metabolic syndrome are disorders of energy balance, which the AMP-activated protein kinase (AMPK) regulates both at the cellular and whole body levels. AMPK switches cells from an anabolic state where nutrients are taken up and stored, to a catabolic state where they are oxidized. Drugs that activate AMPK indirectly (metformin and thiazolidinediones) are now the mainstay of treatment for type 2 diabetes, but more direct AMPK activators may have fewer side effects. However, activating mutations in AMPK can cause heart disease, and it will be important to look for adverse effects in the heart.

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Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction

Cited by 183 publications

References 62 publications

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

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