AMP-activated protein kinase activates transcription of the UCP3 and HKII genes in rat skeletal muscle.
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-beta-d-ribonucleoside (AICAR). AICAR injection activated (P < 0.05) AMPK-alpha 2 ( approximately 2.5-fold) and transcription of the uncoupling protein-3 (UCP3, approximately 4-fold) and hexokinase II (HKII, approximately 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 micro g. 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.
Stoppani
James
J
The John B. Pierce Laboratory and Department of Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06519, USA.
Hildebrandt
Audrey L
AL
Sakamoto
Kei
K
Cameron-Smith
David
D
Goodyear
Laurie J
LJ
Neufer
P Darrell
PD
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051275:Glucose Transporter Type 4; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics*; D007261:Infusions, Intra-Arterial; D007279:Injections, Subcutaneous; D007473:Ion Channels; D019344:Lactic Acid / Q000097:blood; D008297:Male; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D012265:Ribonucleotides; C495694:Slc2a4 protein, rat; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide