Study Links Circadian Rhythm to Oxygen Deficiency, Revealing New Treatment Insights

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The discovery of the time-dependent roles of BMAL1 and HIF-1α provides crucial insights into why certain diseases are more severe at specific times of day.

By Pesach Benson, TPS

In a groundbreaking discovery, researchers at the Weizmann Institute of Science have identified why certain health conditions, such as asthma and heart attacks, tend to strike during the early morning hours.

The findings can inform timing for administering treatments like oxygen therapy, asthma medications or interventions for heart attacks to maximize their effectiveness.

Weizmann Institute scientists led by Professor Gad Asher revealed that the body’s internal circadian clock significantly influences how it responds to oxygen deficiency, potentially explaining the time-dependent nature of many medical emergencies.

The body’s internal circadian clock is a biological system that regulates various physiological processes in a roughly 24-hour cycle, aligning them with the Earth’s day-night rhythm.

It acts as an internal timekeeper, helping the body anticipate and adapt to daily changes in the environment.

The circadian clock regulates the body’s sleep-wake cycle, the release of hormones, the body’s temperature and metabolism and even immune function, among other things.

The Weizmann study, recently published in the peer-reviewed Cell Metabolism journal, focused on the role of BMAL1, a core protein of the circadian clock, in regulating the body’s oxygen response.

BMAL1 collaborates with the hypoxia-inducible factor 1-alpha (HIF-1α) — a protein recognized for its role in cellular adaptation to low oxygen levels. Together, these proteins coordinate the body’s mechanisms for managing oxygen shortages.

It was already known that HIF-1α is crucial for the body’s response to low oxygen levels. However, the researcher found that BMAL1 is also essential for stabilizing and activating HIF-1α during oxygen deficiency.

BMAL1 is not merely a supporting player; it has an independent role in managing the body’s hypoxic response.

When oxygen is abundant, HIF-1α breaks down rapidly. However, in low oxygen conditions, it stabilizes, accumulates, and triggers genes critical for managing hypoxia.

These dual roles suggest BMAL1’s critical involvement in the day-night rhythm of disease susceptibility.

Professor Asher’s team previously observed time-of-day-dependent oxygen responses in liver tissues. To deepen their understanding, they studied genetically modified mice lacking either HIF-1α, BMAL1, or both in their liver tissues.

Under oxygen-deficient conditions, mice missing BMAL1 failed to accumulate HIF-1α as expected, indicating that BMAL1 is essential for HIF-1α function.

Moreover, mice without both proteins exhibited drastically reduced survival rates during nighttime oxygen deprivation, a stark contrast to their better outcomes during daylight.

“These findings highlight how the circadian clock not only adapts to but actively regulates responses to oxygen deficiency,” Asher explained. “The interplay between BMAL1 and HIF-1α is likely the primary mechanism mammals use to cope with low oxygen levels.”

Links Between Liver and Lung Function

The study also explored why mice lacking both proteins in their liver died at night under low-oxygen conditions. Surprisingly, their liver tissues showed only minor damage, insufficient to account for their deaths.

Instead, researchers discovered that these mice had impaired lung function, with blood vessels dilating abnormally and reducing oxygen absorption efficiency — a condition resembling hepatopulmonary syndrome (HPS), a complication often seen in liver disease patients.

This insight led the team to identify elevated nitric oxide levels in the lungs of affected mice, a factor causing the blood vessels to dilate and disrupting normal oxygen transfer. The connection between liver and lung function remains unclear, but preliminary findings suggest an inter-organ communication mechanism involving a specific group of proteins.

“These proteins might play a key role in the liver-lung interaction and could serve as potential therapeutic targets for human patients with hepatopulmonary syndrome,” Asher said.

The discovery of the time-dependent roles of BMAL1 and HIF-1α provides crucial insights into why certain diseases are more severe at specific times of day.

Additionally, the study introduces a genetic mouse model for hepatopulmonary syndrome, offering a new avenue for studying the disease’s underlying mechanisms and developing targeted treatments.

“We now have a unique model to investigate how liver damage disrupts lung function,” Asher said. “This could ultimately lead to therapies for oxygen deficiency-related conditions that vary with the circadian clock.”

Timing medication, surgeries or other interventions for when the body is better equipped to handle oxygen shortages could improve recovery outcomes and reduce complications.

Drugs targeting BMAL1 or HIF-1α could be developed to enhance the body’s ability to manage oxygen deficiency during its most vulnerable periods. And insights from this study could potentially guide daily management strategies for conditions like asthma, chronic obstructive pulmonary disease (COPD), and cardiovascular diseases.