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

Masako Nakano, Taku Hamada, Tatsuya Hayashi, Shin Yonemitsu, Licht Miyamoto, Taro Toyoda, Satsuki Tanaka, Hiroaki Masuzaki, Ken Ebihara, Yoshihiro Ogawa, Kiminori Hosoda, Gen Inoue, Yasunao Yoshimasa, Akira Otaka, Toru Fushiki, Kazuwa Nakao

Research output: Contribution to journalArticle

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Abstract

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 α1 and α2 isoforms of AMPK, the α2 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 α2 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 α2 isoform, we used 5-aminoimidazole-4- carboxamide-1-β-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the α2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the α2 isoform for 90 minutes, but not the α1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the α2 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 α2 activity paralleled the phosphorylation of Thr172, the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase β, 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 α2 isoform of AMPK.

Original languageEnglish
Pages (from-to)300-308
Number of pages9
JournalMetabolism: Clinical and Experimental
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 1 2006
Externally publishedYes

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Aminoimidazole Carboxamide
Ribonucleosides
Facilitative Glucose Transport Proteins
Adenosine Monophosphate
Protein Kinases
Protein Isoforms
Skeletal Muscle
AMP-Activated Protein Kinases
Glucose
Deoxyglucose
Insulin Resistance
Acetyl-CoA Carboxylase
Muscles
4-aminoimidazole
Subcutaneous Injections
Intraperitoneal Injections
Muscle Cells
Phosphotransferases
Extremities
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

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. / Nakano, Masako; Hamada, Taku; Hayashi, Tatsuya; Yonemitsu, Shin; Miyamoto, Licht; Toyoda, Taro; Tanaka, Satsuki; Masuzaki, Hiroaki; Ebihara, Ken; Ogawa, Yoshihiro; Hosoda, Kiminori; Inoue, Gen; Yoshimasa, Yasunao; Otaka, Akira; Fushiki, Toru; Nakao, Kazuwa.

In: Metabolism: Clinical and Experimental, Vol. 55, No. 3, 01.03.2006, p. 300-308.

Research output: Contribution to journalArticle

Nakano, Masako ; Hamada, Taku ; Hayashi, Tatsuya ; Yonemitsu, Shin ; Miyamoto, Licht ; Toyoda, Taro ; Tanaka, Satsuki ; Masuzaki, Hiroaki ; Ebihara, Ken ; Ogawa, Yoshihiro ; Hosoda, Kiminori ; Inoue, Gen ; Yoshimasa, Yasunao ; Otaka, Akira ; Fushiki, Toru ; Nakao, Kazuwa. / 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. In: Metabolism: Clinical and Experimental. 2006 ; Vol. 55, No. 3. pp. 300-308.
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abstract = "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 α1 and α2 isoforms of AMPK, the α2 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 α2 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 α2 isoform, we used 5-aminoimidazole-4- carboxamide-1-β-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the α2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the α2 isoform for 90 minutes, but not the α1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the α2 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 α2 activity paralleled the phosphorylation of Thr172, the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase β, 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 α2 isoform of AMPK.",
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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

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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 α1 and α2 isoforms of AMPK, the α2 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 α2 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 α2 isoform, we used 5-aminoimidazole-4- carboxamide-1-β-d-ribonucleoside (AICAR), which is metabolized in muscle cells and preferentially stimulates the α2 isoform. Subcutaneous administration of 250 mg/kg AICAR activated the α2 isoform for 90 minutes, but not the α1 isoform in hind limb muscles of the C57/B6J mouse. The maximal activation of the α2 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 α2 activity paralleled the phosphorylation of Thr172, the essential residue for full kinase activation, and the activity of acetyl-coenzyme A carboxylase β, 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 α2 isoform of AMPK.

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