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0006 GLUCOCORTICOID SIGNALLING PATHWAYS ARE AFFECTED BY MISTIMED SLEEP, DESPITE CORTISOL REMAINING RHYTHMIC
Ist Teil von
Sleep (New York, N.Y.), 2017-04, Vol.40 (suppl_1), p.A2-A3
Ort / Verlag
US: Oxford University Press
Erscheinungsjahr
2017
Link zum Volltext
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
Abstract
Introduction:
The 24-hour production of cortisol is strongly circadian, being driven, in part, by a rhythmic signal from the suprachiasmatic nuclei via the hypothalamic-pituitary-adrenal axis. In forced desynchrony protocols where sleep is mistimed relative to the central clock, as occurs during shift work, cortisol remains rhythmic, although amplitude can be reduced. Cortisol drives the glucocorticoid receptor signalling pathways, which regulate expression of thousands of genes in peripheral tissues by both direct DNA binding and indirectly by modulating transcription factors. These pathways regulate many processes including peripheral circadian clocks, metabolism, cell development, immune responses and inflammation.
Methods:
In a forced desynchrony study, we collected seven, four-hourly blood samples from 22 volunteers across a 28-hour day while they slept both in-phase and subsequently out-of-phase with their biological clock. We performed whole-genome transcriptome analyses on RNA extracted from these samples and compared expression profiles of components of the glucocorticoid signalling pathways during both sleep conditions using mixed-model ANOVA.
Results:
During forced desynchrony, the phase of the central circadian clock, as indexed by the plasma melatonin and cortisol rhythms, remained largely unchanged by sleeping out of phase. However, when we examined the expression profiles of genes involved in both the direct and indirect glucocorticoid signalling pathways, we observed significant temporal disruption of many components (e.g. HSP70, HSP90, P300, CBP, NCOR1, ERK2, P38, NFKB2) but not all (e.g., SRC, PCAF, ELK1, FKBP4). By contrast, in a separate study where RNA samples were collected during 40h of total sleep deprivation with or without one week of prior sleep restriction, the temporal organisation of these components was not affected.
Conclusion:
This shows that the transcripts associated with glucocorticoid signalling pathways are more sensitive to the temporal disruption caused by mistimed sleep compared to the cortisol rhythm, which remains largely unchanged. Thus, a simple measure of cortisol rhythmicity in, for example, shift workers would not reveal underlying disruption to molecular pathways associated with glucocorticoid signalling. Because glucocorticoid signalling is associated with biological pathways linked with health, this has implications for the increasing numbers of shift workers.
Support (If Any):
BBSRC (UK; BB/F022883, BB/N004981), AFOSR (USA; FA9550-08-1-0080).