α2 isoform-specific activation of 5'adenosine monophosphate-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle.
Metabolism. 2006 Mar; 55(3):300-8.M
5'Adenosine monophosphate-activated protein kinase (AMPK) has been implicated in exercise-induced stimulation of glucose metabolism in skeletal muscle. Although skeletal muscle expresses both the alpha1 and alpha2 isoforms of AMPK, the alpha2 isoform is activated predominantly in response to moderate-intensity endurance exercise in human and animal muscles. The purpose of this study was to determine whether activation of alpha2 AMPK plays a role in increasing the rate of glucose transport, promoting glucose transporter 4 (GLUT4) expression, and enhancing insulin sensitivity in skeletal muscle. To selectively activate the alpha2 isoform, we used 5-aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the alpha2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the alpha2 isoform for 90 minutes, but not the alpha1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the alpha2 isoform was observed 30 to 60 minutes after administration of AICAR and was similar to the activation induced by a 30-minute swim in a current pool. The increase in alpha2 activity paralleled the phosphorylation of Thr(172), the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase beta, a known substrate of AMPK in skeletal muscle. Subcutaneous injection of AICAR rapidly increased, by 30%, the rate of 2-deoxyglucose (2DG) transport into soleus muscle; 2DG transport increased within 30 minutes and remained elevated for 4 hours after administration of AICAR. Repeated intraperitoneal injection of AICAR, 3 times a day for 4 to 7 days, increased soleus GLUT4 protein by 30% concomitant with a significant 20% increase in insulin-stimulated 2DG transport. These data suggest that moderate endurance exercise promotes glucose transport, GLUT4 expression, and insulin sensitivity in skeletal muscle at least partially via activation of the alpha2 isoform of AMPK.
Nakano M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Hamada T
Hayashi T
Yonemitsu S
Miyamoto L
Toyoda T
Tanaka S
Masuzaki H
Ebihara K
Ogawa Y
Hosoda K
Inoue G
Yoshimasa Y
Otaka A
Fushiki T
Nakao K
AMP-Activated Protein KinasesAminoimidazole CarboxamideAnimalsBiological TransportDeoxyglucoseEnzyme ActivationGlucoseGlucose Transporter Type 4InsulinIsoenzymesMiceMice, Inbred C57BLMultienzyme ComplexesMuscle, SkeletalPhysical Conditioning, AnimalProtein Serine-Threonine KinasesRibonucleosidesUp-Regulation
Nakano, Masako, et al. "Α2 Isoform-specific Activation of 5'adenosine Monophosphate-activated Protein Kinase By 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a Physiological Level Activates Glucose Transport and Increases Glucose Transporter 4 in Mouse Skeletal Muscle." Metabolism: Clinical and Experimental, vol. 55, no. 3, 2006, pp. 300-8.
Nakano M, Hamada T, Hayashi T, et al. Α2 isoform-specific activation of 5'adenosine monophosphate-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle. Metabolism. 2006;55(3):300-8.
Nakano, M., Hamada, T., Hayashi, T., Yonemitsu, S., Miyamoto, L., Toyoda, T., Tanaka, S., Masuzaki, H., Ebihara, K., Ogawa, Y., Hosoda, K., Inoue, G., Yoshimasa, Y., Otaka, A., Fushiki, T., & Nakao, K. (2006). Α2 isoform-specific activation of 5'adenosine monophosphate-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle. Metabolism: Clinical and Experimental, 55(3), 300-8.
Nakano M, et al. Α2 Isoform-specific Activation of 5'adenosine Monophosphate-activated Protein Kinase By 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a Physiological Level Activates Glucose Transport and Increases Glucose Transporter 4 in Mouse Skeletal Muscle. Metabolism. 2006;55(3):300-8. PubMed PMID: 16483872.
TY - JOUR T1 - α2 isoform-specific activation of 5'adenosine monophosphate-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside at a physiological level activates glucose transport and increases glucose transporter 4 in mouse skeletal muscle. AU - Nakano,Masako, AU - Hamada,Taku, AU - Hayashi,Tatsuya, AU - Yonemitsu,Shin, AU - Miyamoto,Licht, AU - Toyoda,Taro, AU - Tanaka,Satsuki, AU - Masuzaki,Hiroaki, AU - Ebihara,Ken, AU - Ogawa,Yoshihiro, AU - Hosoda,Kiminori, AU - Inoue,Gen, AU - Yoshimasa,Yasunao, AU - Otaka,Akira, AU - Fushiki,Toru, AU - Nakao,Kazuwa, PY - 2004/10/27/received PY - 2005/09/24/accepted PY - 2006/2/18/pubmed PY - 2006/6/6/medline PY - 2006/2/18/entrez SP - 300 EP - 8 JF - Metabolism: clinical and experimental JO - Metabolism VL - 55 IS - 3 N2 - 5'Adenosine monophosphate-activated protein kinase (AMPK) has been implicated in exercise-induced stimulation of glucose metabolism in skeletal muscle. Although skeletal muscle expresses both the alpha1 and alpha2 isoforms of AMPK, the alpha2 isoform is activated predominantly in response to moderate-intensity endurance exercise in human and animal muscles. The purpose of this study was to determine whether activation of alpha2 AMPK plays a role in increasing the rate of glucose transport, promoting glucose transporter 4 (GLUT4) expression, and enhancing insulin sensitivity in skeletal muscle. To selectively activate the alpha2 isoform, we used 5-aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the alpha2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the alpha2 isoform for 90 minutes, but not the alpha1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the alpha2 isoform was observed 30 to 60 minutes after administration of AICAR and was similar to the activation induced by a 30-minute swim in a current pool. The increase in alpha2 activity paralleled the phosphorylation of Thr(172), the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase beta, a known substrate of AMPK in skeletal muscle. Subcutaneous injection of AICAR rapidly increased, by 30%, the rate of 2-deoxyglucose (2DG) transport into soleus muscle; 2DG transport increased within 30 minutes and remained elevated for 4 hours after administration of AICAR. Repeated intraperitoneal injection of AICAR, 3 times a day for 4 to 7 days, increased soleus GLUT4 protein by 30% concomitant with a significant 20% increase in insulin-stimulated 2DG transport. These data suggest that moderate endurance exercise promotes glucose transport, GLUT4 expression, and insulin sensitivity in skeletal muscle at least partially via activation of the alpha2 isoform of AMPK. SN - 0026-0495 UR - https://www.unboundmedicine.com/medline/citation/16483872/α2_isoform_specific_activation_of_5'adenosine_monophosphate_activated_protein_kinase_by_5_aminoimidazole_4_carboxamide_1_β_D_ribonucleoside_at_a_physiological_level_activates_glucose_transport_and_increases_glucose_transporter_4_in_mouse_skeletal_muscle_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(05)00359-8 DB - PRIME DP - Unbound Medicine ER -
AMP-Activated Protein Kinases
Aminoimidazole Carboxamide
Biological Transport
Glucose Transporter Type 4
Mice, Inbred C57BL
Multienzyme Complexes
Muscle, Skeletal
Physical Conditioning, Animal
Ribonucleosides
Up-Regulation
5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men.
Caffeine acutely activates 5'adenosine monophosphate-activated protein kinase and increases insulin-independent glucose transport in rat skeletal muscles.
Effect of fiber type and nutritional state on AICAR- and contraction-stimulated glucose transport in rat muscle.
Activation of AMPK is essential for AICAR-induced glucose uptake by skeletal muscle but not adipocytes.
Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle.
Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-L1 adipocytes.
Prior serum- and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake.
The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle.
Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle.
5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside stimulates tyrosine hydroxylase activity and catecholamine secretion by activation of AMP-activated protein kinase in PC12 cells.