Circadian regulation of sinoatrial nodal cell pacemaking function: Dissecting the roles of autonomic control, body temperature, and local circadian rhythmicity

Strong circadian (~24h) rhythms in heart rate (HR) are critical for flexible regulation of cardiac pacemaking function throughout the day. While this circadian flexibility in HR is sustained in diverse conditions, it declines with age, accompanied by reduced maximal HR performance. The intricate regulation of circadian HR involves the orchestration of the autonomic nervous system (ANS), circadian rhythms of body temperature (CRBT), and local circadian rhythmicity (LCR), which has not been fully understood. Here, we developed a mathematical model describing ANS, CRBT, and LCR in sinoatrial nodal cells (SANC) that accurately captures distinct circadian patterns in adult and aged mice. Our model underscores how the alliance among ANS, CRBT, and LCR achieves circadian flexibility to cover a wide range of firing rates in SANC, performance to achieve maximal firing rates, while preserving robustness to generate rhythmic firing patterns irrespective of external conditions. Specifically, while ANS dominates in promoting SANC flexibility and performance, CRBT and LCR act as primary and secondary boosters, respectively, to further enhance SANC flexibility and performance. Disruption of this alliance with age results in impaired SANC flexibility and performance, but not robustness. This unexpected outcome is primarily attributed to the age-related reduction in parasympathetic activities, which maintains SANC robustness while compromising flexibility. Our work sheds light on the critical alliance of ANS, CRBT, and LCR in regulating time-of-day cardiac pacemaking function and dysfunction, offering insights into novel therapeutic targets for the prevention and treatment of cardiac arrhythmias.Author summary: The mammalian heart relies on the sinoatrial node, known as the cardiac pacemaker, to orchestrate heartbeats. These heartbeats slow down during sleep and accelerate upon waking, in anticipation of daily environmental changes. The heart’s ability to rhythmically adapt to these 24-hour changes, known as circadian rhythms, is crucial for flexible cardiac performance throughout the day, accommodating various physiological states. However, with aging, the heart’s circadian flexibility gradually weakens, accompanied by a decline in maximal heart rate. Previous studies have implicated the involvement of a master circadian clock and a local circadian clock within the heart, but their time-of-day interactions and altered dynamics during aging remain unclear. In this study, we developed a mathematical model to simulate the regulation of sinoatrial nodal cell pacemaking function by the master and local circadian clocks in adult and aged mice. Our results unveiled distinct roles played by these clocks in determining circadian patterns of sinoatrial nodal cells, shedding light on their critical alliance in regulating time-of-day cardiac pacemaking function and dysfunction.