Biozentrum, University of Basel, Basel, Switzerland.
Leibniz-Institut für Nutztierbiologie, Institut für Genetik und Biometrie, Dummerstorf, Germany.
J Physiol. 2024 Dec;602(23):6373-6402. doi: 10.1113/JP285585. Epub 2024 Jun 8.
Circadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion and metabolism. In certain contexts, the 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 circadian regulator 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 to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts 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 determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. KEY POINTS: Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non-clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.
昼夜节律由主导的中央时钟控制，除了各种外周时钟外，还调节几乎所有的生物过程，包括睡眠-觉醒周期、激素分泌和代谢。在某些情况下，外周振荡的调节和功能可以与中央时钟分离。然而，肌肉内在时钟依赖性调节肌肉功能和代谢的具体机制尚不清楚。我们通过特定基因敲除 Period circadian regulator 2 (Per2) 和 RAR-related orphan receptor alpha (Rorα)，分别研究了骨骼肌肉中分子钟的主要和次要反馈环的扰动的结果。在这两种模型中，都观察到核心时钟基因振荡的减弱，而相位保持不变。此外，这两个环似乎都与胺基群体的动态平衡有关。总的肌肉基因表达出现了高度不同的结果，主要影响 PER2 敲除鼠的昼夜节律性，而 RORα 敲除鼠的非振荡基因则影响代谢组和表型。这些结果突出了分子钟和肌肉可塑性的纠缠，并暗示了不同时钟成分，即主要和次要反馈环，在这种情况下的特定功能。肌肉收缩性和昼夜钟之间的相互作用可能对确定肌肉组织对健康和疾病中扰动的精细适应至关重要。关键点：分子钟的主要和次要反馈环的特定扰动会导致肌肉代谢和功能的特定结果。通过删除 Per2（主要环）或 Rorα（次要环），核心时钟基因的振幅减弱，而相位没有变化。PER2 缺失对主要反馈环的扰动主要影响肌肉基因的振荡。RORα 的敲除及其随后对次要环的调制导致大量非时钟基因和蛋白质的异常表达。PER2 和 RORα 的缺失以昼夜节律的方式影响肌肉代谢和收缩功能，突出了分子钟在调节肌肉可塑性方面的核心作用。
