Abstract
ObjectiveEvidence for AMP-activated protein kinase (AMPK)-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to a chronic lack of AMPK function. To study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice. MethodsTamoxifen-inducible and muscle-specific AMPKα1/α2 double KO mice (AMPKα imdKO) were generated by using the Cre/loxP system, with the Cre under the control of the human skeletal muscle actin (HSA) promoter. ResultsDuring treadmill running at the same relative exercise intensity, AMPKα imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPKα in adult mice promptly reduced maximal running speed and muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole-body substrate utilization, and muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion of AMPKα subunits in adult mice. ConclusionsInducible deletion of AMPKα subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise but is dispensable for regulating muscle glucose uptake, FA oxidation, and substrate utilization during exercise.
Highlights
Physical activity is associated with a marked increase in muscle metabolism and energy turnover [1]
3.1 Time-course of skeletal muscle-specific deletion of AMPKα1 and α2 In order to define the earliest time-point at which full deletion of the catalytic AMPKα1 and α2 protein had occurred in myofibers, we investigated the AMPK subunit levels 1, 3 and 8 weeks after tamoxifen315 induced gene deletion. 1 week after the last tamoxifen injection, the mRNA content of AMPKα1 and AMPKα2 in extensor digitorum longus (EDL) muscle was reduced to ~58% and ~0%, respectively, compared to tamoxifen-treated AMPKα double-floxed control mice (Fig 1A and 1B)
In addition, insulin-stimulated signaling in EDL muscle at the level of Akt (Akt Thr308) and its downstream target TBC1D4 (TBC1D4 Thr642) were comparable between genotypes, suggesting that insulin signaling to GLUT4 translocation was regulated in muscles from the two genotypes (Fig 2F-H). These findings demonstrate that acute deletion of AMPK catalytic activity in skeletal muscle does not affect whole body insulin action or the ability of insulin to stimulate glucose uptake in isolated skeletal muscle
Summary
Physical activity is associated with a marked increase in muscle metabolism and energy turnover [1]. The increased intramyocellular AMP/ATP ratio leads to activation of 5’-AMP-activated protein kinase (AMPK) [3], which promotes catabolic processes and inhibits anabolic processes in order to normalize the cellular energy status [4]. On this basis, skeletal muscle AMPK is proposed to function as a cellular energy sensor that is activated during exercise and acts as a central mediator of cellular signaling to maintain energy homeostasis. Acute pharmacological activation of AMPK in rodent muscle by different pharmacological agents
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