Loss of endogenous circadian clock function in mice alters respiratory cycle timing in a time of day- and sex-specific manner

Resting breathing and ventilatory chemoreflexes are regulated in a 24-hr manner by the endogenous circadian clock. However, it is unclear how circadian biology influences different phases of the breath-to-breath respiratory cycle which are predominantly controlled by pontomedullary regions of the brainstem. Here, we performed whole-body plethysmography during quiet wakefulness in young adult male and female mice lacking the core clock gene Brain and Muscle Arnt-like 1 (BMAL1) to determine the extent to which the molecular clock affects respiratory cycle timing and ventilatory airflow mechanics. Breath waveform analysis revealed that male BMAL1 knockout (KO) mice exhibit time of day-specific differences in inspiratory and expiratory times, total cycle length, end inspiratory pause, relaxation time, and respiratory rate compared to wild-type littermates. Notably, changes in respiratory pattern were not observed in female BMAL1 KO mice when compared to wild-type females. Additionally, BMAL1 deficiency did not disrupt overall minute ventilation or peak airflow in either sex, suggesting total ventilatory function during quiet wakefulness is preserved. Taken together, these findings indicate that genetic disruption of the circadian clock in mice elicits sex-specific changes in respiratory cycle timing.