bims-ciryme 2022-11-06 papers

Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2211142119

Coupling-dependent metabolic ultradian rhythms in confluent cells.

Shuzhang Yang, Shin Yamazaki, Kimberly H Cox, Yi-Lin Huang, Evan W Miller, Joseph S Takahashi.

Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.

Keywords: cellular metabolism; gap junctions; ion channels; membrane potential; ultradian rhythms

DOI: https://doi.org/10.1073/pnas.2211142119

Nat Commun. 2022 Nov 02. 13(1): 6580

Tempo: an unsupervised Bayesian algorithm for circadian phase inference in single-cell transcriptomics.

Benjamin J Auerbach, Garret A FitzGerald, Mingyao Li.

The circadian clock is a 24 h cellular timekeeping mechanism that regulates human physiology. Answering several fundamental questions in circadian biology will require joint measures of single-cell circadian phases and transcriptomes. However, no widespread experimental approaches exist for this purpose. While computational approaches exist to infer cell phase directly from single-cell RNA-sequencing data, existing methods yield poor circadian phase estimates, and do not quantify estimation uncertainty, which is essential for interpretation of results from very sparse single-cell RNA-sequencing data. To address these unmet needs, we introduce Tempo, a Bayesian variational inference approach that incorporates domain knowledge of the clock and quantifies phase estimation uncertainty. Through simulations and analyses of real data, we demonstrate that Tempo yields more accurate estimates of circadian phase than existing methods and provides well-calibrated uncertainty quantifications. Tempo will facilitate large-scale studies of single-cell circadian transcription.

DOI: https://doi.org/10.1038/s41467-022-34185-w

J Endocr Soc. 2022 Oct 26. 6(12): bvac153

Endogenous Diurnal Patterns of Adrenal and Gonadal Hormones During a 24-Hour Constant Routine After Simulated Shift Work.

Monica R Kelly, Fiona Yuen, Brieann C Satterfield, Richard J Auchus, Shobhan Gaddameedhi, Hans P A Van Dongen, Peter Y Liu.

Context: Night-shift work causes circadian misalignment, predicts the development of metabolic diseases, and complicates the interpretation of hormone measurements.
Objective: To investigate endogenous circadian rhythms, dissociated from behavioral and environmental confounds, in adrenal and gonadal steroids after simulated shift work.
Methods: Fourteen healthy adults (ages 25.8 ± 3.2 years) were randomized to 3 days of night or day (control) shift work followed by a constant routine protocol designed to experimentally unveil rhythms driven endogenously by the central circadian pacemaker. Blood was sampled every 3 hours for 24 hours during the constant routine to concurrently obtain 16 Δ4 steroid profiles by mass spectrometry. Cosinor analyses of these profiles provided mesor (mean abundance), amplitude (oscillation magnitude), and acrophase (peak timing).
Results: Night-shift work marginally increased cortisol by 1 μg/dL (P = 0.039), and inactive/weak derivatives cortisone (P = 0.003) and 18-hydroxycortisol (P < 0.001), but did not alter the mesor of potent androgens testosterone and 11-ketotestosterone. Adrenal-derived steroids, including 11-ketotestosterone (P < 0.01), showed robust circadian rhythmicity after either day- or night-shift work. In contrast, testosterone and progesterone showed no circadian pattern after both shift work conditions. Night-shift work did not alter the amplitude or acrophase of any of the steroid profiles.
Conclusion: Experimental circadian misalignment had minimal effects on steroidogenesis. Adrenal steroids, but not gonadal hormones, showed endogenous circadian regulation robust to prior shift schedule. This dichotomy may predispose night-shift workers to metabolic ill health. Furthermore, adrenal steroids, including cortisol and the main adrenal androgen 11-ketostosterone, should always be evaluated during the biological morning whereas assessment of gonadal steroids, particularly testosterone, is dependent on the shift-work schedule.

Keywords: circadian misalignment; healthy young adults; internal desynchrony; reproductive health; sex steroids

DOI: https://doi.org/10.1210/jendso/bvac153