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Tissue-specific body clocks
The body’s circadian rhythm is critical for regulating hormone secretion, wake cycles, and metabolic processes. Its function is well established, but in recent years another layer of complexity to the body’s timing system has been proposed: tissue-specific clocks.
Tissue-specific clocks would enable circadian adjustments at the local level, driven by molecular signals. The stimuli that trigger such adaptations for specific tissues remain to be determined.
Scientists from the University of Manchester have investigated the link between clocks in articular cartilage and the brain. Our earlier work revealed internal body clocks in intervertebral discs and cartilage that dampen aging, says Professor King-Jun Meng, a body clock expert at the University of Manchester and 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 was published in Nature Communications.
Why do we wake up taller?
Meng and his 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 the lights were turned on. Control mice, which were spared the ongoing program, were housed in the same room but in a cage.
Treadmill exercise in mice two hours after the start of the normal resting phase resulted in a large phase advance of skeletal clocks for up to eight hours. Interestingly, this exercise protocol did not alter the circadian rhythm of the SCN, leading to uncoupling of the central and skeletal clocks, the authors write.
After the 12-day program, the mice were euthanized so that Meng and colleagues could create explant cultures and perform RNA sequencing analyses. Cartilage and intervertebral disc (IVD) explants were compressed or exposed to higher osmolarity culture medium. Both of these interventions resulted in a synchronization effect.
Direct exposure ex vivo mechanical loading or hyperosmolarity of the cartilage tissue and IVD was sufficient to induce circadian oscillations, thereby ruling out the involvement of systemic factors in clock synchronization 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 the flexibility for cartilage/IVD clocks to decouple from the suprachiasmatic nucleus (SCN) clock to cope with changing environmental demands.
As we move every day, water is squeezed out of the IVD and articular cartilage. The overall effect is that we are a little shorter when the evening comes.  this causes tissue osmolarity to increase because the same amount of mineral is now dissolved in less water, so the actual concentration increases, says lead author Dr Michal Dudek from the University of Manchester. Cells sense this change in osmolarity and synchronize clocks within these skeletal tissues.
Consistent exercise is beneficial for the elderly population
Further research will be needed to determine whether human cartilage and the IVD react in the same way, but the researchers say it is highly likely.
Our results showed that physical activities in the morning, associated with daily sleep/wake cycle patterns, transmit timing information from the light-sensitive central clock in the brain to the weight-bearing skeletal tissue. In effect, it’s telling your skeletal system it’s time to wake up, Meng says.
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When the alignment gets out of whack, it can lead to adverse effects on physical health, Meng adds: If you’re constantly changing your exercise times, you may be more prone to this desynchronization. However, if you change when you exercise, but then stick with that pattern for a while, we show that your body clocks will eventually realign with each other, and you’ll adapt accordingly.
The researchers also studied clocks in the tissues of older animals, which maintain their sensitivity to daily exercise patterns. As such, walking groups organized for older people may be more beneficial to their health if they occur at a similar time each day, Meng suggests.
Professor Judith Hoiland, spine/IVD research expert at the University of Manchester and co-senior author, talks about how the research will benefit our understanding of skeletal ageing: Among the many health challenges, age-related musculoskeletal decline and its adverse consequences represent a great burden on individuals  Importantly, we have identified a novel clock mechanism underlying skeletal aging, which could have far-reaching implications for understanding frailty and designing more effective treatment timing of exercise and physiotherapy to maintain good skeletal health and mobility.
Reference: Dudek M, Pathiranage DRJ, Bano-Otalora B, et al. Mechanical stress and hyperosmolarity as a diurnal cue to reset skeletal circadian clocks. Nat Comms. 2023;14(1):7237. doi: 10.1038/s41467-023-42056-1
This article is a reprint of a University of Manchester press release. The material is arranged according to length and content.
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