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

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2010

J Biol Chem 2010 Nov 26;285(48):37198-209. Epub 2010 Sep

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

Campbell, DJ;Chen, ZP;Dzamko, NL;Galic, S;Hewitt, K;Honeyman, J;Jorgensen, SB;Kemp, BE.;Koentgen, F;Koopman, R;Lynch, GS;Naim, T;O'Neill, HM;Schertzer, JD;Scott, J;Steinberg, GR;Vandenderen, BJ;Watt, MJ

Department of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

Service type: Knockout mice

Abstract

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.

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