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Physiological rhythms are central to life. Mammalian behavior and metabolism are organized around the day and night by the regulated action of cell-autonomous clocks that exist throughout our bodies. At the core of this molecular clockwork are multiple coupled feedback loops that generate sustained circadian rhythms in gene expression to ultimately orchestrate mammalian physiology. In this work we provide evidence for the role of metabolism in regulating the core clock. We present genes involved in energetic and redox pathways which we identified to be essential for the robustness of cellular timekeepers to temperature fluctuations. We developed the first computational model for circadian redox oscillations that contributes to the understanding of how cellular redox balance might adjust circadian rates in response to perturbations and convey timing information to the core molecular oscillator. Moreover, we show that our mathematical model can be coupled with prior published models of the transcriptional clockwork resulting in 1:1 entrainment. This experimental-theoretical approach exemplifies the need of a dynamic analysis at the system level to understand complex biological processes and provides insights into how basic timekeeping mechanisms are integrated into cellular physiology. Such knowledge might highlight new ways by which functional consequences of circadian timekeeping can be explored in the context of human health and disease.

Physiological rhythms are central to life. Mammalian behavior and metabolism are organized around the day and night by the regulated action of cell-autonomous clocks that exist throughout our bodies. At the core of this molecular clockwork are multiple coupled feedback loops that generate sustained circadian rhythms in gene expression to ultimately orchestrate mammalian physiology. In this work we provide evidence for the role of metabolism in regulating the core clock. We present genes involved in energetic and redox pathways which we identified to be essential for the robustness of cellular timekeepers to temperature fluctuations. We developed the first computational model for circadian redox oscillations that contributes to the understanding of how cellular redox balance might adjust circadian rates in response to perturbations and convey timing information to the core molecular oscillator. Moreover, we show that our mathematical model can be coupled with prior published models of the transcriptional clockwork resulting in 1:1 entrainment. This experimental-theoretical approach exemplifies the need of a dynamic analysis at the system level to understand complex biological processes and provides insights into how basic timekeeping mechanisms are integrated into cellular physiology. Such knowledge might highlight new ways by which functional consequences of circadian timekeeping can be explored in the context of human health and disease.

Physiological rhythms are central to life. Mammalian behavior and metabolism are organized around the day and night by the regulated action of cell-autonomous clocks that exist throughout our bodies. At the core of this molecular clockwork are multiple coupled feedback loops that generate sustained circadian rhythms in gene expression to ultimately orchestrate mammalian physiology. In this work we provide evidence for the role of metabolism in regulating the core clock. We present genes involved in energetic and redox pathways which we identified to be essential for the robustness of cellular timekeepers to temperature fluctuations. We developed the first computational model for circadian redox oscillations that contributes to the understanding of how cellular redox balance might adjust circadian rates in response to perturbations and convey timing information to the core molecular oscillator. Moreover, we show that our mathematical model can be coupled with prior published models of the transcriptional clockwork resulting in 1:1 entrainment. This experimental-theoretical approach exemplifies the need of a dynamic analysis at the system level to understand complex biological processes and provides insights into how basic timekeeping mechanisms are integrated into cellular physiology. Such knowledge might highlight new ways by which functional consequences of circadian timekeeping can be explored in the context of human health and disease.

Bibliography: p. [217]-218

This article is from Arthritis Research & Therapy , volume 14 . Abstract Introduction: Circadian rhythms play an important role in the body and in single cells. Rhythms of molecular clocks have not been investigated in synovial fibroblasts (SF) of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). The study was initiated to fill this gap and to study effects of interleukin (IL)-1β/tumor necrosis factor (TNF) on rhythmicity in synovial fibroblasts of RA and OA patients. Methods: The presence of BMAL-1, CLOCK, Period 1 and Period 2 proteins in synovial tissue was investigated by immunofluorescence. The presence of mRNA of molecular clocks was studied during 72 h by qPCR. Characteristics of rhythms were studied with time series analysis. Results: BMAL-1, CLOCK, Period 1 and Period 2 proteins were abundantly present in synovial tissue of OA, RA and controls. Receiving synovial tissue at different operation time points during the day (8:00 am to 4:00 pm) did not reveal a rhythm of BMAL-1 or Period 1 protein. In OASF and RASF, no typical rhythm curve of molecular clock mRNA was observed. Time series analysis identified a first peak between 2 and 18 hours after synchronization but a period was not detectable due to loss of rhythm. TNF inhibited mRNA of CLOCK, Period 1 and Period 2 in OASF, while IL-1β and TNF increased these factors in RASF. This was supported by dose-dependently increased levels in MH7A RA fibroblasts. In RASF, IL-1β and TNF shifted the first peak of BMAL-1 mRNA to later time points (8 h to 14 h). Conclusion: Rhythmicity is not present in primary OASF and RASF, which is unexpected because fibroblasts usually demonstrate perfect rhythms during several days. This might lead to uncoupling of important cellular pathways.

Includes bibliographical references (pages 224-235) and index