Bmal1 Mediates Sex Differences in Parasympathetic Control of Heart Rate

The molecular clock contributes to the endogenous physiological rhythms at multiple levels of regulation, including rhythms that are crucial for the regulation of cardiovascular function and autonomic control. While the role of the molecular clock and time of day in physiological function has become more apparent, the underlying mechanisms for how the clock regulates many physiological functions are not understood. Here we investigated the role of Bmal1, a core component of the molecular clock, in mediating rhythms in heart rate (HR) and autonomic control in male and female rats across the day, testing the hypothesis that time of day, sex, and Bmal1 contribute to cardiovascular and autonomic rhythms. Bmal1-knockout (Bmal1-KO) and wildtype (WT) littermates were implanted with a telemetry transmitter in the abdominal aorta and allowed to recover for 10 days in a temperature and humidity controlled 12:12hr light/day cycle with ad libitum access to food and water. Blood pressure (BP) and HR were recorded for 2 minutes every 10 minutes at 1000 samples/second for 24 hours. BP and HR data underwent variability analysis in Ponemah v 6.2. Diurnal HR rhythms, assessed by 12 hour averages from the inactive (I, zeitgeber time 0-11) and active (A, zeitgeber time 12-23) periods, were present in all groups (WT Males I: 351±13 vs A: 420±13 BPM; KO Males I: 356±6 vs A: 396±5 BPM, p<0.05 by 2 way ANOVA; WT Females I: 362±7 vs A: 419±6 BPM; KO Females I: 375±5 vs A: 410±5 BPM, p<0.05 by 2-way ANOVA). Spectral analysis of HR variability found that root mean of the square successive differences (rMSSD), an indirect measurement of parasympathetic control over HR, revealed time- and sex- dependent differences in rats. In male rats, loss of Bmal1 resulted in higher rMSSD across both the active and inactive period compared to WT controls (Inactive: WT 4.0±0.6 vs KO 5.5±0.4 ms, p<0.05; Active: WT 2.9±0.2 vs KO 4.6±0.5 ms, p<0.05). In females, Bmal1-KO rats had lower rMSSD in the inactive period compared to WT rats (WT: 4.1±0.3 vs KO: 3.0±0.3 ms, p<0.05), but had similar rMSSD during the active period to WT controls (WT: 3.0±0.2 vs KO: 2.7±0.3 ms, p>0.05). rMSSD was higher during the inactive period in all groups except KO females compared to their respective active period (p<0.05), suggesting a clear time of day dependent difference in parasympathetic output. Together, these data suggest that parasympathetic control of heart rate may be mediated by the molecular clock in a sex-dependent manner. Funding: American Heart Association 24CDA1046338 to MKR This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.