Alignment of exercise timing with intrinsic circadian clocks for intervertebral disc health and matrix homeostasis

Among the many health challenges associated with ageing, degeneration of the soft tissue intervertebral discs (IVDs) in the spine is a primary feature of the ageing skeleton, contributing to pain and loss of mobility. However, we do not fully understand why age increases susceptibility to disc degeneration. The IVD separates our bony vertebraes and provides important cushioning and load-absorbing functions during regular daily cycles of activities. Recently, our group discovered functional 24-hour internal clocks in the IVD. This body clock becomes weakened and imprecise with age and its disruption through clock gene deletion leads to tissue damage and loss of characteristics of human IVD. This project aims to understand how our body clocks in the spine are regulated on a daily basis and why they weaken with age. We will establish how daily mechanical loading patterns of the spine due to physical activity keep the IVD clocks in synchrony with the rhythmic environment. We will also assess the importance of timing of exercise on spine health. Specifically, we will use a novel IVD "clockless" mouse model, treadmill exercise and cultures of cells and tissues to address the following questions: 1) Is the clock in the signalling centre of the IVD important for tissue health? 2) Do IVDs respond differently to mechanical loading depending on the time-of-day? 3) How mechanical loading keeps the IVD body clocks aligned with the external day/night cycle?

This research builds on our recent novel discoveries and holds strong potential to advance our understanding of IVD circadian biology and promote tissue health against ageing. As such, there is an enormous potential for improving health and quality of life throughout our life course. Moreover, our findings emphasize the importance of exercise timing for better skeletal health, which will have a long-lasting impact on the health and well-being of the nation. This is particularly important because the greying of the population and the ever-increasing demands of our modern 24/7 society frequently disrupt our body clocks which can adversely impact on our health, wellbeing and productivity.

Circadian clocks drive ~24-hour rhythms in nearly all aspects of our physiology and behaviour. Changes of circadian rhythms during ageing underpin many of the age-associated physical and mental health problems. Among these, degeneration of the fibro-cartilaginous intervertebral discs (IVDs) is a primary feature of the ageing skeleton, contributing to pain and loss of mobility. Our recent work has demonstrated cell autonomous circadian clocks in IVD which control rhythmic expression of more than 600 genes, many are known key players in IVD tissue homeostasis. Genetic disruption of the intrinsic IVD clock in mice leads to tissue damage characteristic of human disc degeneration (fibrosis and ossification). More recently, we have shown that mechanical loading and osmotic challenge associated with physical exercise is a potent resetting signal for the IVD. Importantly, exercise has been proposed as a beneficial intervention for several age-related musculoskeletal conditions. However, little is known about the importance of the timing of exercise for musculoskeletal health. Building on our recent exciting discoveries, we now aim to combine our unique IVD-"clockless" transgenic mouse models, ex vivo IVD explant and cultures of IVD cells to establish the time-of-day dependent responses of the IVD to mechanical loading and the underlying mechanisms, and the consequences of chronic misaligned exercise timing on IVD health. This research holds strong potential to improve our understanding of how ageing, a sedentary lifestyle and shift work impact on skeletal system and may prompt a new paradigm of time-prescribed circadian aligned exercise schedule for better skeletal health and improved tissue homeostasis and regeneration.