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Peek, Clara Bien; Levine, Daniel C.; Cedernaes, Jonathan; Taguchi, Akihiko; Kobayashi, Yumiko; Tsai, Stacy J.; Bonar, Nicolle A.; McNulty, Maureen R.; Ramsey, Kathryn Moynihan; Bass, Joseph
Cell metabolism, 01/2017, Letnik: 25, Številka: 1Journal Article
Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1−/− myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia. HIF1α bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1α in Vhl−/− cells altered circadian transcription. Finally, induction of clock and HIF1α target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia. Display omitted •Clock disruption in skeletal muscle reduces HIF1α activity and anaerobic glycolysis•Genetic and hypoxic stabilization of HIF alters circadian transcription•Maximal induction of HIF in response to exercise occurs in the early active period Peek et al. demonstrate that circadian clock disruption impairs oxygen sensing through HIF and anaerobic glycolysis in skeletal muscle. In turn, HIF upregulation lengthens the circadian period. HIF is primed by the clock to respond more robustly to exercise during the early active period.
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