Presenting Author:

Clara Peek, Ph.D.

Principal Investigator:

Joseph Bass, M.D.

Department:

Medicine

Keywords:

circadian, clock, hypoxia, hypoxia inducible factor (HIF), skeletal muscle, BMAL1, exercise, anaerobic glycolysis, lacta... [Read full text] circadian, clock, hypoxia, hypoxia inducible factor (HIF), skeletal muscle, BMAL1, exercise, anaerobic glycolysis, lactate, bHLH-PAS [Shorten text]

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B44 - Basic Science

Circadian Clock-HIF1α Interaction Mediates Oxygenic Metabolism in Skeletal Muscle

Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. Here 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 bi-directional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia.