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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/E1032    most recent 90510.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vieira, E. Articles by Mahlapuu, M. Search for Related Content PubMed PubMed Citation Articles by Vieira, E. Articles by Mahlapuu, M.

Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm; ²Discovery Research, Biovitrum, Gothenburg; and ³Lundberg Laboratory for Diabetes Research, Göteborg Universtiy, Gothenburg, Sweden

Submitted 17 June 2008 ; accepted in final form 24 August 2008

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)₃ subunit is involved in the regulation of peripheral circadian clock function. AMPK3 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 AMPK₃ subunit knockout mice. Our results indicate AMPK heterotrimeric complexes containing the AMPK₃ subunit may play a specific role in linking circadian oscillators and energy metabolism in skeletal muscle.

adenosine 5'-monophosphate-activated protein kinase; clock genes; circadian rhythm