The intricate dance of daily rhythms in mammalian behaviour and physiology is governed by a multi-oscillator circadian system, finely tuned by environmental cues such as light and feeding. Recent advancements in circadian research have unveiled a fascinating layer of complexity—tissue niche-dependent physiological time cues that empower tissues with the ability to adjust their circadian phase based on local signals.
In a groundbreaking study, researchers have shed light on the elusive nature of these stimuli, revealing that daily patterns of mechanical loading and associated osmotic challenges serve as bona fide tissue niche-specific time cues, orchestrating circadian clock phase and amplitude adjustments in cartilage and intervertebral disc (IVD) tissues both in vivo and in tissue explant cultures.Â
The daily rhythms of Earth’s environment, encompassing cycles of light and darkness, temperature fluctuations, and the availability of food, exert profound influences on the physiology and behaviour of living organisms. To ensure optimal adaptation to these environmental cues, organisms have evolved an internal circadian clock, a cell-intrinsic timing mechanism. The alignment of internal circadian rhythms with external environmental cues, known as entrainment, is crucial for organismal health and survival.Â
In mammals, the central pacemaker—the Suprachiasmatic Nuclei (SCN) in the hypothalamus—coordinates and adjusts peripheral clocks in major body organs. Light, a potent entrainment factor, resets the central clock, which, in turn, signals through neuronal connections or hormonal cues to synchronize peripheral clocks. However, the evolution of local tissue clocks, allowing for flexibility in response to specific physiological demands, challenges the notion of a top-down control solely from the SCN.Â
One compelling piece of evidence supporting the flexibility of local tissue clocks is the uncoupling of circadian clocks in the liver and other tissues from the SCN under restricted feeding conditions. Building on this, the researchers hypothesized that mechanical loading might be a key entraining factor for circadian rhythms in skeletal tissues.
To test this, they employed a treadmill as a methodology of choice, allowing precise control over the time of exercise, intensity, and volume. Results from PER2::Luc reporter mice adapted to daily treadmill running revealed an intriguing decoupling effect, with the circadian phase of clocks in cartilage and IVD tissues advancing by approximately 8 hours, while the SCN remained unaffected.Â
To ensure that these effects were not influenced by potential metabolic or systemic effects of exercise, the researchers directly tested the role of mechanical loading using an ex vivo PER2::Luc tissue explant culture model and the FlexCell compression system. The short loading regime induced a robust increase in circadian rhythm amplitude in cartilage, maintained for at least three more days.
Furthermore, the timing of compression within the 24-hour cycle proved critical, with compression at the peak of PER2::Luc resulting in a significant amplitude increase, while compression at other phases caused significant phase delays or advances. The magnitude of the force of compression also influenced the phase shift of the cartilage circadian rhythm.Â
The study expanded its focus to osmotic challenges, revealing that hyperosmolarity, but not hypo-osmolarity, reset the circadian clocks in young and aging skeletal tissues. Genome-wide expression analysis pinpointed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes.Â
This research offers compelling evidence for the role of daily patterns of mechanical loading and osmotic challenges as tissue niche-specific time cues, maintaining skeletal circadian rhythms in synchrony. The findings open new avenues for understanding the complex interplay between environmental cues, mechanical stimuli, and circadian regulation, with potential implications for optimizing circadian rhythms to promote skeletal health and overall well-being.Â
Journal Reference Â
Dudek, M., Pathiranage, D.R.J., Bano-Otalora, B. et al. Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks. Nat Commun 14, 7237 (2023). https://doi.org/10.1038/s41467-023-42056-1Â
