Abstract
A bout of exercise potently stimulates skeletal muscle energy metabolism. The ATP turnover may rise up to0 ~100 fold compared to the resting state and this presents a substantial stress on skeletal muscle ATP regeneration. To prepare for future events of metabolic stress, the muscle increases its metabolic capacity through several mechanisms. Some of the most important are increases in muscle capillarization and in expression of metabolic and mitochondrial proteins that transport and metabolize glucose and fatty acids.
The protein AMPK is a trimeric protein composed of an α-, β- and a y-subunit. It is proposed to be involved in acute exercise-induced regulation of substrate metabolism as well as the adaptations in muscle protein expression that arise from repeated bouts of exercise, i.e. exercise training. Exercise regulates a plethora of signaling pathways in muscle which includes the activation of AMPK. A highly specific activation of AMPK can be attained with the pharmacological compound AICAR. Similar to exercise, an acute dose of AICAR increases muscle glucose uptake and repeated stimulation with AICAR increases the metabolic capacity of rodent muscle. However, in genetically mutated mice lacking functional AMPK (KO/KD), muscle glucose uptake is not increased by AICAR. Neither do the muscles of these mice attain metabolic and mitochondrial adaptations after repeated AICAR treatments. The absent responses in AMPK KO/KD mice suggest that AMPK mediates the AICAR signal and propose that AMPK could also regulate muscle metabolism during exercise and long-term adaptations to exercise training.
However, responses to exercise and exercise training are largely normal in AMPK KO/KD mice. At first hand this could mean that AMPK is not important to exercise/exercise training metabolic regulation and profile. In most AMPK deficient models only a single isoform of the two aatalytic α-subunits has been targeted for inactivation. But turning to other models of disrupted AMPK-function such as the AMPKβ1β2M-KO mouse or the LKB1 KO mouse (indirect effect on AMPK-function), it has been found that exercise-regulated metabolism and exercise training-induced adaptations are abnormal. This could be due to a more complete ablation of AMPK function and perhaps related to the catalytic properires of the α-subunits.
In study 1 we show that deletion of both AMPKα subunits in skeletal muscle of mice decreases exerciseinduced fatty acid utilization, supposedly due to a lower CD36 protein expression and an abolished TBC1D1 Ser237 phosphorylation believed to impair CD36 translocation. The second study reveals that AMPKα1 and – α2 are not essential to acquiring adaptations in expression/activity of most investigated proteins in response to 4 weeks of voluntary running wheel exercise training. However, the acute exercise-induced increase in mRNA expression of several metabolic and mitochondrial marker genes is impaired in the mice lacking AMPKα1 and α2. In addition to the two studies and some currently unpublished data this thesis presents a review of AMPK in skeletal muscle exercise-induced metabolic regulation and exercise traininginduced adaptations.
The protein AMPK is a trimeric protein composed of an α-, β- and a y-subunit. It is proposed to be involved in acute exercise-induced regulation of substrate metabolism as well as the adaptations in muscle protein expression that arise from repeated bouts of exercise, i.e. exercise training. Exercise regulates a plethora of signaling pathways in muscle which includes the activation of AMPK. A highly specific activation of AMPK can be attained with the pharmacological compound AICAR. Similar to exercise, an acute dose of AICAR increases muscle glucose uptake and repeated stimulation with AICAR increases the metabolic capacity of rodent muscle. However, in genetically mutated mice lacking functional AMPK (KO/KD), muscle glucose uptake is not increased by AICAR. Neither do the muscles of these mice attain metabolic and mitochondrial adaptations after repeated AICAR treatments. The absent responses in AMPK KO/KD mice suggest that AMPK mediates the AICAR signal and propose that AMPK could also regulate muscle metabolism during exercise and long-term adaptations to exercise training.
However, responses to exercise and exercise training are largely normal in AMPK KO/KD mice. At first hand this could mean that AMPK is not important to exercise/exercise training metabolic regulation and profile. In most AMPK deficient models only a single isoform of the two aatalytic α-subunits has been targeted for inactivation. But turning to other models of disrupted AMPK-function such as the AMPKβ1β2M-KO mouse or the LKB1 KO mouse (indirect effect on AMPK-function), it has been found that exercise-regulated metabolism and exercise training-induced adaptations are abnormal. This could be due to a more complete ablation of AMPK function and perhaps related to the catalytic properires of the α-subunits.
In study 1 we show that deletion of both AMPKα subunits in skeletal muscle of mice decreases exerciseinduced fatty acid utilization, supposedly due to a lower CD36 protein expression and an abolished TBC1D1 Ser237 phosphorylation believed to impair CD36 translocation. The second study reveals that AMPKα1 and – α2 are not essential to acquiring adaptations in expression/activity of most investigated proteins in response to 4 weeks of voluntary running wheel exercise training. However, the acute exercise-induced increase in mRNA expression of several metabolic and mitochondrial marker genes is impaired in the mice lacking AMPKα1 and α2. In addition to the two studies and some currently unpublished data this thesis presents a review of AMPK in skeletal muscle exercise-induced metabolic regulation and exercise traininginduced adaptations.
| Original language | English |
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| Place of Publication | Copenhagen |
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| Publisher | Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen |
| Number of pages | 108 |
| ISBN (Print) | 978-87-7611-930-0 |
| Publication status | Published - 2015 |