Daily Scheduled Exercise Helps To Sync Body Clock

Tissue-specific body clocks

The body’s circadian rhythm is critical for regulating hormonal secretion, sleep‒wake cycles and metabolic processes. Its function is well established, but a further layer of complexity to the “timekeeping” system of the body has been proposed in recent years: that of tissue-specific clocks.

Tissue-specific clocks would allow for circadian adjustments to be made on a local level, prompted by molecular signals. The stimuli triggering such adjustments for specific tissues is yet to be established.

Scientists at the University of Manchester have explored the relationship between clocks in joint cartilage and the brain. “Our earlier work discovered internal body clocks in intervertebral discs and cartilage that dampen with aging,” says Professor Qing-Jun Meng, a body clock expert from The University of Manchester and a senior author of the paper. “Importantly, healthy cartilage and intervertebral discs have no nerves and no blood supply, so until now it was not clear how their internal clocks synchronize with the brain.”

The research is published in Nature Communications.

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Meng and colleagues used mouse models to investigate how internal clocks synchronize with the brain without nerves or blood supply.

The mice undertook a 12-day treadmill program, where running was performed two hours after lights on. Control mice, who were spared from the running program, were placed in the same room but in a cage.

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“Treadmill running exercise in mice two hours after the beginning of normal resting phase led to a large phase advance of the skeletal clocks of up to eight hours. Interestingly, this exercise protocol did not change the SCN circadian rhythm, leading to an uncoupling of the central and skeletal clocks,” the authors write.

After the 12-day program, the mice were euthanized so Meng and colleagues could create explant cultures and run RNA-sequencing analyses. The cartilage and intervertebral disc (IVD) explants were compressed or exposed to higher osmolarity culture medium. Both of these interventions resulted in a “synchronizing” effect.

“Direct exposure of ex vivo cartilage and IVD tissues to mechanical loading or hyperosmolarity was sufficient to induce circadian oscillations, thus excluding the involvement of systemic factors in synchronization of the clock by treadmill running,” the authors explain. “Based on our findings, we propose these daily physiological inputs as key tissue-specific zeitgebers. This specificity may allow flexibility for cartilage/IVD clocks to be uncoupled from the suprachiasmatic nuclei (SCN) clock to cope with changing environmental needs.”

While we move around each day, water is pressed out of the IVDs and joint cartilage. The overall effect is that we are a tad shorter by the time evening comes around. “[…] this causes increase in osmolarity of the tissue because the same amount of minerals is now dissolved in less water so the actual concentration increases,” says Dr. Michal Dudek, lead author from The University of Manchester. “Cells sense this change in osmolarity and synchronize the clocks within these skeletal tissues.”

Consistent exercise beneficial for elderly populations

Further research will be required to establish whether human cartilage and IVDs respond in the same way, but the researchers say it is a “high probability”.

“Our results showed that physical activities in the morning, associated with daily patterns of sleep/wake cycle, convey timing information from the light-sensitive central clock in the brain to the weight-bearing skeletal tissues. In effect it’s telling your skeletal system it’s time to wake up,” says Meng.

When the alignment uncouples, it can result in adverse effects on physical health, Meng adds: “If you are constantly changing the time you exercise, you may be more prone to this desynchronization. However, if you change when you exercise, but then maintain that regime for some time, we show that your body clocks will eventually re-align with each other, and you will adapt to it.”

The researchers also studied the clocks in tissues from older animals, which maintain their responsiveness to daily patterns of exercise. “As such, walking groups organised for older people could be more beneficial for their health if they happen at a similar time every day,” suggests Meng.

Professor Judith Hoyland, expert in spine/IVD research at The University of Manchester and co-senior author, discusses how the research will benefit our understanding of the aging skeleton: “Among the many health challenges, the age-related musculoskeletal decline – and its adverse consequences – is a major burden to individuals […] Importantly, we have identified a new clock mechanism underlying skeletal aging, which could have far-reaching impacts on understanding frailty and designing more efficient treatment timing of exercise and  physiotherapy to maintain good skeletal health and mobility.”

Reference: Dudek M, Pathiranage DRJ, Bano-Otalora B, et al. Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks. Nat Comms. 2023;14(1):7237. doi: 10.1038/s41467-023-42056-1

This article is a rework of a press release issued by University of Manchester. Material has been edited for length and content.