Chronic activation of 5′-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle

Abstract

This study was designed to determine whether chronic chemical activation of AMP-activated protein kinase (AMPK) would increase glucose transporter GLUT-4 and hexokinase in muscles similarly to periodic elevation of AMPK that accompanies endurance exercise training. The adenosine analog, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), has previously been shown to be taken up by cells and phosphorylated to form a compound (5-aminoimidazole-4-carboxamide ribonucleotide) that mimics the effect of AMP on AMPK. A single injection of AICAR resulted in a marked increase in AMPK in epitrochlearis and gastrocnemius/plantaris muscles 60 min later. When rats were injected with AICAR (1 mg/g body wt) for 5 days in succession and were killed 1 day after the last injection, GLUT-4 was increased by 100% in epitrochlearis muscle and by 60% in gastrocnemius muscle in response to AICAR. Hexokinase was also increased approximately 2. 5-fold in the gastrocnemius/plantaris. Gastrocnemius glycogen content was twofold higher in AICAR-treated rats than in controls. Chronic chemical activation of AMPK, therefore, results in increases in GLUT-4 protein, hexokinase activity, and glycogen, similarly to those induced by endurance training.

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

“…During chronic AMPK activation, AMPKstimulated glucose uptake may override inhibition of glycogen synthase by AMPK, resulting in enhanced glycogen storage. Similar effects of glycogen supercompensation have been previously observed in AICARtreated Sprague-Dawley rats [32]. However, further AMPK activation through acute AICAR stimulation resulted in a decrease in glycogen levels in myotubes from control and R225W carriers.…”

“…The increase in plasma fatty acids in R225W carriers during exercise may indicate a blunted increase in fatty acid uptake in muscle in response to exercise, stemming in turn from a greater proportional reliance on endogenous glucose and glycogen fuel stores in the muscle of individuals with the PRKAG3 R225W mutation. The mechanism responsible for a greater glucose uptake in R225W carriers during exercise may be elevated skeletal muscle GLUT4 levels, which has been previously demonstrated in Sprague-Dawley rats chronically treated with AICAR [32]. However, GLUT4 (also known as SLC2A4) expression in the control and R225W primary human myotubes was undetectable via quantitative RT-PCR (data not shown).…”

“…While the mechanisms underlying the AMPK-mediated increases in glucose uptake have not been fully elucidated, AMPK has been shown to phosphorylate and activate TBC1 domain family, member 4 (TBC1D4) and the IRS-1, both of which stimulate GLUT4 translocation [30,31]. Additionally, chronic AMPK activation in Sprague-Dawley rats through treatment with AICAR increases skeletal muscle levels of GLUT4 and hexokinase [32]. The present study characterises for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding the-AMPKγ 3 subunit, PRKAG3 R225W.…”

AMP-activated protein kinase regulates the expression of monocarboxylate transporter 4 in skeletal muscle

“…Several studies have shown that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMPK activator, activates glucose transport and increases the expression of glucose transporter 4 (GLUT4) and several metabolic enzymes in skeletal muscle (Buhl et al, 2001;Holmes et al, 1999Holmes et al, , 2005Ojuka et al, 2002;Stoppani et al, 2002;Winder et al, 2000;Zheng et al, 2001). It has been reported that an increase in glucose uptake induced by AICAR results in increased lactic acid production in isolated rat skeletal muscle (Miyamoto et al, 2007).…”

Regulation of skeletal muscle GLUT-4 expression by exercise and nutritional stimuli

“…AMPK is activated during exercise and has been termed a master metabolic switch because it phosphorylates key target proteins that control the flux through metabolic pathways. Chronic activation of AMPK by injection of the adenosine analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) into rats results in an increase in GLUT-4 protein in vivo 21) ; the same pattern occurs when isolated rat muscles are exposed to AICAR in vitro 22) . Furthermore, AMPK phosphorylates GEF 23) and the transcription repressor histone deacetylase 5 (HDAC5) 24) .…”