Jones Aaron A, Marino Gabriella M, Arble Deanna M
Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin, United States.
Am J Physiol Endocrinol Metab. 2024 Jul 1;327(1):E111-E120. doi: 10.1152/ajpendo.00111.2024. Epub 2024 Jun 5.
The master circadian clock, located in the suprachiasmatic nuclei (SCN), organizes the daily rhythm in minute ventilation (V̇e). However, the extent that the daily rhythm in V̇e is secondary to SCN-imposed O and CO cycles (i.e., metabolic rate) or driven by other clock mechanisms remains unknown. Here, we experimentally shifted metabolic rate using time-restricted feeding (without affecting light-induced synchronization of the SCN) to determine the influence of metabolic rate in orchestrating the daily V̇e rhythm. Mice eating predominantly at night exhibited robust daily rhythms in O consumption (V̇o), CO production (V̇co), and V̇e with similar peak times (approximately ZT18) that were consistent with SCN organization. However, feeding mice exclusively during the day separated the relative timing of metabolic and ventilatory rhythms, resulting in an approximately 8.5-h advance in V̇co and a disruption of the V̇e rhythm, suggesting opposing circadian and metabolic influences on V̇e. To determine if the molecular clock of cells involved in the neural control of breathing contributes to the daily V̇e rhythm, we examined V̇e in mice lacking BMAL1 in Phox2b-expressing respiratory cells (i.e., BKOP mice). The ventilatory and metabolic rhythms of predominantly night-fed BKOP mice did not differ from wild-type mice. However, in contrast to wild-type mice, exclusive day feeding of BKOP mice led to an unfettered daily V̇e rhythm with a peak time aligning closely with the daily V̇co rhythm. Taken together, these results indicate that both daily V̇co changes and intrinsic circadian time-keeping within Phox2b respiratory cells are predominant orchestrators of the daily rhythm in ventilation. The master circadian clock organizes the daily rhythm in ventilation; however, the extent that this rhythm is driven by SCN regulation of metabolic rate versus other clock mechanisms remains unknown. We report that metabolic rate alone is insufficient to explain the daily oscillation in ventilation and that neural respiratory clocks within Phox2b-expressing cells additionally optimize breathing. Collectively, these findings advance our mechanistic understanding of the circadian rhythm in ventilatory control.
位于视交叉上核（SCN）的主生物钟调节着分钟通气量（V̇e）的每日节律。然而，V̇e的每日节律在多大程度上继发于SCN施加的氧气和二氧化碳循环（即代谢率），或由其他生物钟机制驱动，目前尚不清楚。在这里，我们通过限时进食实验性地改变代谢率（不影响SCN的光诱导同步），以确定代谢率在协调每日V̇e节律中的影响。主要在夜间进食的小鼠在氧气消耗（V̇o）、二氧化碳产生（V̇co）和V̇e方面表现出强烈的每日节律，其峰值时间相似（约为ZT18），这与SCN的组织情况一致。然而，只在白天给小鼠喂食会使代谢节律和通气节律的相对时间分离，导致V̇co提前约8.5小时，并破坏V̇e节律，这表明生物钟和代谢对V̇e有相反的影响。为了确定参与呼吸神经控制的细胞的分子生物钟是否对每日V̇e节律有贡献，我们检测了在表达Phox2b的呼吸细胞中缺乏BMAL1的小鼠（即BKOP小鼠）的V̇e。主要在夜间进食的BKOP小鼠的通气和代谢节律与野生型小鼠没有差异。然而，与野生型小鼠不同的是，只在白天给BKOP小鼠喂食会导致不受限制的每日V̇e节律，其峰值时间与每日V̇co节律紧密对齐。综上所述，这些结果表明，每日V̇co的变化和Phox2b呼吸细胞内的内在生物钟计时都是通气每日节律的主要调节因素。主生物钟调节通气的每日节律；然而，这种节律在多大程度上由SCN对代谢率的调节与其他生物钟机制驱动，仍不清楚。我们报告说，仅代谢率不足以解释通气的每日振荡，并且表达Phox2b的细胞内的神经呼吸生物钟还能额外优化呼吸。总的来说，这些发现推进了我们对通气控制中昼夜节律机制的理解。
