The role of circadian rhythms and redox signalling in musculoskeletal stem cell ageing

Skeletal muscle stem cell function is essential for tissue regeneration in response to injury and disease, which significantly declines with ageing. To be able to effectively use stem cell therapies to combat age-related tissue degeneration, it is important to understand the critical determinants of stem cell regulation. Recent work has demonstrated the role for circadian rhythms in regulating adult stem cell responses to external cues from the microenvironment. Circadian (24h) rhythms are evolutionary conserved timing mechanisms that keep our tissue physiology in tune with the external environment and their disruption (as a result of ageing, genetic variation, or shift work) is associated with age-related tissue deterioration. Emerging data has shown that many environmental stimuli can reset circadian clocks via redox mechanisms, suggesting an important role for interactions between clocks and redox properties of the cellular niche in stem cell regulation. However, how these redox-transduction processes couple with cellular clock machinery to optimally direct skeletal muscle stem cell behaviour is currently not known.
We have previously published that NRF2-mediated redox signalling is subject to circadian regulation. This new project will investigate the role of NRF2 in skeletal muscle stem cell maintenance, differentiation and ageing by examining its regulation of epigenetic and clock factors using human myogenic precursors and transgenic animal models. This project will use a range of cross-disciplinary and 'state-of the art' techniques in order to perform cutting-edge research, including analyses of protein expression (western blotting, immunohistochemistry, proteomics), gene expression (qPCR, RNAseq) and protein-DNA interactions (ChiP) and clock gene rhythms (real-time bioluminescent imaging). Epigenetic tools will be used to perform gain- or loss-of-function approaches. Mathematical modelling of molecular pathways will enable us to model key proteins involved in integrating spatial and timing cues that control stem cell function.