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More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα

ABSTRACT: Circadian rhythms, governed by the dominant central as well as various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion, and metabolism. In certain contexts, regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period 2 (Per2) and RAR-related orphan receptor alpha (RORα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem involved in the homeostasis of amine groups. Very divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the Per2, and non-oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity, and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determine a finely tuned adaptation of muscle tissue to perturbations in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE243522 | GEO | 2024/01/02

REPOSITORIES: GEO

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Project description:The peripheral circadian oscillator plays an essential role in synchronizing local physiology to operate in a circadian manner via regulation of the expression of clock-controlled genes. In the murine uterus, the endometrial stromal cells undergo proliferation and differentiation into decidual cells in response to ovarian steroids and blastocyst implantation at the early stage of pregnancy. The circadian clock genes are attenuated in the decidualizing cells only 2 days after implantation. The present study aimed to evaluate the circadian rhythms of clock genes and clock-controlled genes expressed in the rat uterus endometrial stromal cells (UESCs) during the stage of implantation. The real-time monitoring system of Per2 promoter activity was employed to precisely evaluate the generation of circadian rhythms in the UESCs prepared from transgenic rats constructed with mouse Per2 promoter-destabilized luciferase reporter gene (Per2-dLuc). During monitoring Per2-dLuc oscillation after synchronization with dexamethasone, total RNA was isolated from the cultured UESCs at four-time points (6-h interval) in the first to second phases and cDNA was synthesized. cRNA was synthesized from the double strand cDNA and hybridized on a DNA microarray. RT-qPCR was performed to confirm the expression of core clock genes revealed by DNA microarray analysis. Several clock genes such as Bmal1, Rev-erbα, and Per2 displayed significant rhythms. Of 12,252 genes showing significantly expression, 7,235 genes displayed significant alterations (p < 0.05). These genes were related to growth factors, transcription factors, receptors, channels, and enzymes. Some candidates as clock-controlled genes were evaluated by using RNA interference to Bmal1 mRNA. Down-regulation of Igf1 gene expression was observed by Bmal1 silencing, whereas the expression of Inhβa, Fas, and Caspase3 were significantly increased. These results indicate that clock-controlled genes are up- or down-regulated in rat UESCs during the stage of decidualization. DNA microarray analysis coupled with RNA interference will be helpful to understand the physiological roles of some oscillating genes in blastocyst implantation and placenta formation. The circadian clock positively or negatively regulates the expression of clock-controlled genes, including growth factors and apoptosis-related factors. To search the clock-controlled genes expressed during the period of implantation, we analyzed the clock genes and clock-controlled genes expressed in cultured uterus endometrial stromal cells prepared from pregnant rats at the stage of implantation using DNA microarray technology. We used transgenic rats constructed with mouse Per2 promoter-destabilized luciferase (Per2-dLuc) reporter gene to precisely adjust the time of gene expression. In addition, several genes of significantly expressed genes including growth factor genes and apoptosis-related genes were analyzed using RNA interference to Bmal1 mRNA whether these were controlled under circadian clockwork.

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More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα

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