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1 The John B. Pierce Laboratory and 2 Department of Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06519; and 3 Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215
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-
-D-ribonucleoside (AICAR). AICAR injection activated (P < 0.05)
AMPK-
2 (~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 · min1
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.
5-aminoimidazole-4-carboxamide ribonucleoside; single-leg arterial infusion; rat; AMP kinase phosphorylation
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