Glycogen-Dependent Effects of 5-Aminoimidazole-4-Carboxamide (AICA)-Riboside on AMP-Activated Protein Kinase and Glycogen Synthase Activities in RatSkeletal Muscle

Abstract

1 5-AMP-activated protein kinase (AMPK) functions as a metabolic switch in mammalian cells and can be artificially activated by 5-aminoimidazole-4-carboxamide (AICA)-riboside. AMPK activation during muscle contraction is dependent on muscle glycogen concentrations, but whether glycogen also modifies the activation of AMPK and its possible downstream effectors (glycogen synthase and glucose transport) by AICA-riboside in resting muscle is not known. Thus, we have altered muscle glycogen levels in rats by a combination of swimming exercise and diet and investigated the effects of AICA-riboside in the perfused rat hindlimb muscle. Two groups of rats, one with super-compensated muscle glycogen content (ϳ200 -300% of normal; high glycogen [HG]) and one with moderately lowered muscle glycogen content (ϳ80% of normal; low glycogen [LG]), were generated. In both groups, the degree of activation of the ␣2 isoform of AMPK by AICA-riboside depended on muscle type (white gastrocnemius Ͼ Ͼ red gastrocnemius > soleus). Basal and AICA-riboside-induced ␣2-AMPK activity were markedly lowered in the HG group (ϳ50%) compared with the LG group. Muscle 2-deoxyglucose uptake was also increased and glycogen synthase activity decreased by AICA-riboside. Especially in white gastrocnemius, these effects, as well as the absolute activity levels of AMPK-␣2, were markedly reduced in the HG group compared with the LG group. The inactivation of glycogen synthase by AICA-riboside was accompanied by decreased gel mobility and was eliminated by protein phosphatase treatment. We conclude that acute AICA-riboside treatment leads to phosphorylation and deactivation of glycogen synthase in skeletal muscle. Although the data do not exclude a role of other kinases/phosphatases, they suggest that glycogen synthase may be a target for AMPK in vivo. Both basal and AICA-riboside-induced AMPK-␣2 and glycogen synthase activities, as well as glucose transport, are depressed when the glycogen stores are plentiful. Because the glycogen level did not affect adenine nucleotide concentrations, our data suggest that glycogen may directly affect the activation state of AMPK in skeletal muscle. Diabetes 51:284 -292, 2002

Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells

“…It has been reported that AMP kinase can directly phosphorylate and inactivate glycogen synthase in vitro [31]. It has also been demonstrated that the β-subunit of AMP kinase contains a motif that can bind glycogen [32,33], and increased glycogen binding is correlated with decreased AMP kinase activation in response to AICAR [34]. These data suggest that AMP kinase activation promotes depletion of cellular glycogen stores, and this is consistent with our results showing that adiponectin activates AMP kinase and reduces glycogen synthesis in L6 rat skeletal muscle cells.…”

PGC-1α and exercise in the control of body weight

“…49,71 On the contrary, glycogen levels are elevated in response to PGC-1a and an inverse correlation between muscle glycogen content and AMPK activity has been established. 47,72,73 AMPK has a glycogenbinding domain on its b-subunit and there is evidence that glycogen---directly or indirectly---inhibits AMPK activity. 74 Furthermore, by tightly balancing ROS levels, PGC-1a might antagonize the activation of ROS-dependent signaling pathways in skeletal muscle.…”

Ischemia-induced activation of AMPK does not increase glucose uptake in glycogen-replete isolated working rat hearts

“…For example, there is an inverse correlation between glycogen content and AMPK activity in both skeletal (47,48) and cardiac muscle (24). Indeed, abundant stores of glycogen depress activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) in skeletal muscles, as well as the associated acceleration of glucose uptake (47).…”

“…For example, there is an inverse correlation between glycogen content and AMPK activity in both skeletal (47,48) and cardiac muscle (24). Indeed, abundant stores of glycogen depress activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) in skeletal muscles, as well as the associated acceleration of glucose uptake (47). An examination of the role of glycogen availability on the relationship between myocardial ischemia, glucose uptake, and AMPK activation was achieved using an additional group of hearts (G depleted) in which glycogen levels were reduced to values reported for hearts that are either perfused without insulin, perfused with glucose as the sole energy substrate, or where the preischemic aerobic baseline period may be too short to permit adequate resynthesis of glycogen.…”