TY - JOUR

T1 - AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle

AU - Stoppani, James

AU - Hildebrandt, Audrey L.

AU - Sakamoto, Kei

AU - Cameron-Smith, David

AU - Goodyear, Laurie J.

AU - Darrell Neufer, P.

PY - 2002/12/1

Y1 - 2002/12/1

N2 - AMP-activated protein kinase (AMPK) has recently emerged as a key signaling protein in skeletal muscle, coordinating the activation of both glucose and fatty acid metabolism in response to increased cellular energy demand. To determine whether AMPK signaling may also regulate gene transcription in muscle, rats were given a single subcutaneous injection (1 mg/g) of the AMP analog 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR). AICAR injection activated (P < 0.05) AMPK-α2 (∼2.5-fold) and transcription of the uncoupling protein-3 (UCP3, ∼4-fold) and hexokinase II (HKII, ∼10-fold) genes in both red and white skeletal muscle. However, AICAR injection also elicited (P < 0.05) an acute drop (60%) in blood glucose and a sustained (2-h) increase in blood lactate, prompting concern regarding the specificity of AICAR on transcription. To maximize AMPK activation in muscle while minimizing potential systemic counterregulatory responses, a single-leg arterial infusion technique was employed in fully conscious rats. Relative to saline-infused controls, single-leg arterial infusion of AICAR (0.125, 0.5, and 2.5 μg·g-1·min-1 for 60 min) induced a dose-dependent increase (2- to 4-fold, P < 0.05) in UCP3 and HKII transcription in both red and white skeletal muscle. Importantly, AICAR infusion activated transcription only in muscle from the infused leg and had no effect on blood glucose or lactate levels. These data provide evidence that AMPK signaling is linked to the transcriptional regulation of select metabolic genes in skeletal muscle.

AB - AMP-activated protein kinase (AMPK) has recently emerged as a key signaling protein in skeletal muscle, coordinating the activation of both glucose and fatty acid metabolism in response to increased cellular energy demand. To determine whether AMPK signaling may also regulate gene transcription in muscle, rats were given a single subcutaneous injection (1 mg/g) of the AMP analog 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR). AICAR injection activated (P < 0.05) AMPK-α2 (∼2.5-fold) and transcription of the uncoupling protein-3 (UCP3, ∼4-fold) and hexokinase II (HKII, ∼10-fold) genes in both red and white skeletal muscle. However, AICAR injection also elicited (P < 0.05) an acute drop (60%) in blood glucose and a sustained (2-h) increase in blood lactate, prompting concern regarding the specificity of AICAR on transcription. To maximize AMPK activation in muscle while minimizing potential systemic counterregulatory responses, a single-leg arterial infusion technique was employed in fully conscious rats. Relative to saline-infused controls, single-leg arterial infusion of AICAR (0.125, 0.5, and 2.5 μg·g-1·min-1 for 60 min) induced a dose-dependent increase (2- to 4-fold, P < 0.05) in UCP3 and HKII transcription in both red and white skeletal muscle. Importantly, AICAR infusion activated transcription only in muscle from the infused leg and had no effect on blood glucose or lactate levels. These data provide evidence that AMPK signaling is linked to the transcriptional regulation of select metabolic genes in skeletal muscle.

KW - 5-Aminoimidazole-4-carboxamide ribonucleoside

KW - AMP kinase phosphorylation

KW - Rat

KW - Single-leg arterial infusion

UR - http://www.scopus.com/inward/record.url?scp=0036889017&partnerID=8YFLogxK

M3 - Journal article

C2 - 12388122

AN - SCOPUS:0036889017

VL - 283

SP - E1239-E1248

JO - A J P: Endocrinology and Metabolism (Online)

JF - A J P: Endocrinology and Metabolism (Online)

SN - 1522-1555

IS - 6 46-6

ER -