Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle.
Circadian clocks coordinate physiological, behavioral, and biochemical events with predictable daily environmental changes by a self-sustained transcriptional feedback loop. CLOCK and ARNTL are transcriptional activators that regulate Per and Cry gene expression. PER and CRY inhibit their own transcription, and their turnover allows this cycle to restart. The transcription factors BHLHB2 and BHLHB3 repress Per activation, whereas orphan nuclear receptors of the NR1D and ROR families control Arntl expression. Here we show the AMP-activated protein kinase (AMPK)gamma(3) subunit is involved in the regulation of peripheral circadian clock function. AMPKgamma3 knockout (Prkag3(-/-)) mice or wild-type littermates were injected with saline or an AMPK activator, 5-amino-4-imidazole-carboxamide riboside (AICAR), and white glycolytic gastrocnemius muscle was removed for gene expression analysis. Genes involved in the regulation of circadian rhythms (Cry2, Nr1d1, and Bhlhb2) were differentially regulated in response to AICAR in wild-type mice but remained unaltered in Prkag3(-/-) mice. Basal expression of Per1 was higher in Prkag3(-/-) mice compared with wild-type mice. Distinct diurnal changes in the respiratory exchange ratio (RER) between the light and dark phase of the day were observed in wild-type mice but not Prkag3(-/-) mice. In summary, the expression profile of clock-related genes in skeletal muscle in response to AICAR, as well as the diurnal shift in energy utilization, is impaired in AMPKgamma(3) subunit knockout mice. Our results indicate AMPK heterotrimeric complexes containing the AMPKgamma(3) subunit may play a specific role in linking circadian oscillators and energy metabolism in skeletal muscle.
Vieira
Elaine
E
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Nilsson
Elisabeth C
EC
Nerstedt
Annika
A
Ormestad
Mattias
M
Long
Yun Chau
YC
Garcia-Roves
Pablo M
PM
Zierath
Juleen R
JR
Mahlapuu
Margit
M
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology; D056931:Cryptochromes; D004268:DNA-Binding Proteins / Q000235:genetics; D005420:Flavoproteins / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006593:Hexokinase / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D007473:Ion Channels / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D000071247:Uncoupling Protein 3
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D004268:DNA-Binding Proteins; D005420:Flavoproteins; D051275:Glucose Transporter Type 4; D006593:Hexokinase; D018398:Homeodomain Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D012265:Ribonucleotides; D015534:Trans-Activators; D014157:Transcription Factors; D000071247:Uncoupling Protein 3; C491539:Bhlhe40 protein, mouse; C538967:Cry2 protein, mouse; C498262:Nr1d1 protein, mouse; C539023:Per1 protein, mouse; C485290:Ppargc1a protein, mouse; C495693:Slc2a4 protein, mouse; C538944:Clock protein, mouse; C526221:Prkag3 protein, mouse; C031143:AICA ribonucleotide