Abstract
Oscillations in circadian metabolism are crucial to the well being of organism. Our understanding of metabolic rhythms has been greatly enhanced by recent advances in high-throughput systems biology experimental techniques and data analysis. In an in vitro setting, metabolite rhythms can be measured by time-dependent sampling over an experimental period spanning one or more days at sufficent resolution to elucidate rhythms. We hypothesized that cellular metabolic effects over such a time course would be influenced by both oscillatory and circadian-independent cell metabolic effects. Here we use nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling of mammalian cell culture media of synchronized U2 OS cells containing an intact transcriptional clock. The experiment was conducted over 48 h, typical for circadian biology studies, and samples collected at 2 h resolution to unravel such non-oscillatory effects. Our data suggest specific metabolic activities exist that change continuously over time in this settting and we demonstrate that the non-oscillatory effects are generally monotonic and possible to model with multivariate regression. Deconvolution of such non-circadian persistent changes are of paramount importance to consider while studying circadian metabolic oscillations.
Highlights
IntroductionThe physiology and behavior of most complex organisms is regulated in a circadian manner
The physiology and behavior of most complex organisms is regulated in a circadian manner.Chronic disruption of this rhythm can lead to a cascade of maladaptive effects including cognitive and psychiatric dysfunction, metabolic disorders and cancer [1,2,3,4,5,6,7]
The innate circadian rhythm of the cellular metabolism (Circadian process) and second, a linear continuous change of the cellular metabolism over the two days of collection dictated by the properties of the secretome, i.e. nutrient availablity and waste metabolite build-up (Metabolic process)
Summary
The physiology and behavior of most complex organisms is regulated in a circadian manner. Recent results from our group showed that ectopic MYC oncogene expression significantly affects oscillation in glucose in metabolism and glutaminolysis [11] While studies of such rhythms are increasingly important, the metabolic context of general metabolite changes and metabolic status over the sampling time required for high time-resolution circadian rhythm studies has not been described. The innate circadian rhythm of the cellular metabolism (Circadian process) and second, a linear continuous change of the cellular metabolism over the two days of collection dictated by the properties of the secretome, i.e. nutrient availablity and waste metabolite build-up (Metabolic process) We investigated these effects by profiling the metabolites of the cell culture media using nuclear magnetic resonance (NMR) spectroscopy. These results suggest that analysis of oscillatory metabolic rhythms must be corrected for linear growth/secretion effects
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