Clinical Chronobiology: A Timely Consideration in Critical Care Medicine

Helen McKenna; Gijsbertus T. J. van der Horst; Irwin Reiss; Daniel Martin


Crit Care. 2018;22(124) 

In This Article

The Molecular Networking of Circadian Rhythms

Our planet rotates through 360° every 24 h, creating an inescapable oscillation between light and darkness. Most life on Earth evolved under the influence of this day–night cycle, leading to the parallel oscillation of behaviour, physiology and metabolism throughout the 24-h period (diurnal rhythms). These rhythms are generated by cell-intrinsic molecular clocks with a periodicity of approximately (circa) 24 h (diem), for which reason they are called "circadian" clocks. Temporal compartmentalisation of functions according to predictable daily fluctuations in the environment has been vital to the survival of even the most primitive organisms, such as the single-celled Synechococcus cyanobacterium, which separates its two fundamental metabolic processes (photosynthesis and nitrogen fixation) by time rather than place.[3] In complex organisms such as humans, every cell has its own circadian clock. The cellular circadian rhythm is generated via a molecular network of transcriptional–translational feedback loops, with one cycle taking approximately 24 h to complete.[4] In short, the Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain And Muscle ARNT-Like 1 (BMAL1) genes encode a heterodimeric transcription factor known as CLOCK/BMAL1 that activates E-box promoter containing genes, including the Period (PER1 and PER2) and Cryptochrome (CRY1 and CRY2) core clock genes and a variety of clock-controlled genes (CCG) that couple the circadian oscillator to physiological and metabolic pathways. Once formed, PER/CRY protein complexes translocate to the nucleus where they inhibit CLOCK/BMAL1-mediated transcription of E-box genes, including their own.[5] Between 5 and 20% of all gene transcription in mammalian cells is controlled by this molecular oscillator depending on tissue type.[6] The oscillating transcriptome directly influences most biological pathways, ultimately shaping measurable indices such as body temperature, brain wave activity, cardiovascular and respiratory functions, coagulation and immunity.[7]