Metabolic Consequences of Chronic Exposure to Combined Intermittent Hypoxia and Sleep Fragmentation in Mice

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Abstract Rationale: Obstructive sleep apnea (OSA) is characterized by repeating episodes of airway collapse that cause chronic intermittent hypoxia (CIH) and sleep disruption due to recurrent arousals, called chronic sleep fragmentation (CSF). OSA is associated with high economic and health burdens due to increased risk of cardiovascular and metabolic diseases. However, the combined effects of intermittent hypoxia (IH) and sleep fragmentation (SF) (IH+SF) remain largely unexplored. We aim to study the effects of IH and SF combined in one chamber to access the metabolic function in a murine model. Methods: Adult male C57BL/6 mice (3 months old) were exposed to either IH+SF or normoxia (room air, RA) for 6 months. The IH protocol alternated between FiO2 21% and FiO2 6% every 90 seconds for 12 hours per day, during the light cycle (06:00h-18:00h). SF was induced by 2-minute intervals between mechanical sweeps, totaling 30 events per hour during the rest period. Body weight, blood pressure, glucose tolerance (GTT), insulin tolerance (ITT), total energy expenditure (TEE), respiratory exchange ratio (RER), and water intake were measured using an indirect calorimetry system. Electrical cardiac activity was recorded from non-anesthetized mice via ECGenie equipment (Mouse Specifics Inc.), capturing heart rate (HR), RR interval, PQ interval, PR interval, QT interval, QTc interval, QRS complex, and ST segment. Results: The IH+SF group exhibited a significant reduction in body weight compared to the RA group (p < 0.05). Systolic and diastolic blood pressures were significantly elevated in the IH+SF group (p < 0.05). GTT results showed impaired glucose metabolism in the IH+SF group, with higher glucose levels at all post-administration time points. Similarly, ITT demonstrated reduced insulin sensitivity, indicating metabolic dysregulation. TEE was significantly increased in the IH+SF group, reflecting heightened metabolic activity. The RER was lower, suggesting a shift toward greater fat oxidation in response to IH+SF. Heart rate variability (HRV), RR intervals, and the coefficient of variation (CV) were significantly higher in the IH+SF group compared to controls, indicating cardiac autonomic disturbances. Conclusion: Chronic exposure to IH+SF, simulating OSA conditions, impairs metabolic regulation and cardiovascular health. These findings suggest that OSA may contribute to metabolic disorders, such as insulin resistance and hypertension. Understanding these effects is critical for clinical management. Further research is necessary to investigate the underlying mechanisms and to develop potential therapeutic strategies for OSA-associated metabolic disturbances.

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