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Musculoskeletal function around the clock: The effects of age, exercise and shift work


Institute of Ageing and Chronic Disease

About the Project

BACKGROUND: Optimal skeletal muscle function is essential for tissue regeneration in response to injury and disease, which significantly declines with ageing and chronic disease1,4. To be able to effectively use novel lifestyle therapies to combat age-related muscle tissue deterioration, it is important to understand the critical determinants of muscle regulation. One such important factor is related to timing signals within the body, which all tissues and cells can sense by altering their downstream gene/protein expression and physiology2. 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 dysfunction and disease3,5. Emerging data has shown that many timed environmental stimuli, such as light, exercise and nutrients, can reset circadian clocks via redox mechanisms, suggesting an important role for feedback interactions between tissue clocks and redox properties in circadian regulation4. However, how these redox-responsive processes couple with cellular clock machinery to optimally regulate skeletal muscle function is not known. Also, it is not known how human muscle function is affected in individuals with disrupted circadian cycles such as night-shift work.

GOALS: We have previously published that NRF2-mediated redox signaling is subject to circadian regulation5. Our recent data has discovered a non-canonical role for NRF2 in regulating clock genes in skeletal muscle cells and tissues. This project will investigate the following hypotheses: 1) mouse skeletal muscle show altered circadian regulation of NRF2 and its target genes with age, 2) muscle clock changes with age can be partially rescued by time-scheduled exercise in mice 3) human muscle clock is altered by altered circadian cycles such as night-shift work.

TRAINING: This exciting project will use a wide range of cross-disciplinary and ’state-of the art’ techniques in order to perform cutting-edge bioscience research. Young and old clock:luciferase reporter mice and real-time bioluminescent imaging will be used to track muscle clock gene rhythms outside the body. Muscle histology will be analysed using immunohistochemistry and microscopy. To investigate regulation of NRF2 and its targets, we will study temporal protein expression (western blotting, proteomics), gene expression (qPCR, RNA-seq) and protein-protein and protein-DNA interactions (ChiP, co-immunoprecipitation). Finally, human participants will be recruited engaged in night shift work (e.g. nurses) and will be assessed for their musculoskeletal function and gait6,7.

SUPERVISORY TEAM: This project is a collaboration between the primary supervisor Dr Vanja Pekovic-Vaughan (circadian redox biology), Dr Aphrodite Vasilaki (muscle physiology) and Dr Kris d’Atout (biomechanics and gait analyses). The project will have close collaborations with academics and researchers associated with CIMA (MRC-Versus Arthritis Centre for Integrated Musculoskeletal Ageing), where the student will have the opportunity to undergo further lab training (https://www.cimauk.org/)

ENVIRONMENT: The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

Candidate Requirements: The successful candidate should have, or expect to have, an Honours Degree at 2.1 or above (or equivalent). Candidates whose first language is not English should have an IELTS score of 6.5 or equivalent. This project is most suitable to students with an undergraduate or Master’s degree in any of Life and Health Science disciplines.

Informal Enquiries to: Dr Vanja Pekovic-Vaughan ()

To apply: Please send your CV and a covering letter to Dr. Vanja-Pekovic Vaughan with a copy to

Funding Notes

There is NO funding attached to this project. The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £10,000 per year. Details of costs can be found on the University website.

References

1. Adult stem cell maintenance around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?' 2018 Biogerontology 19(6):497-517
2. Comparing Circadian Dynamics in Primary Derived Stem Cells from Different Sources of Human Adult Tissue. 2017 Stem Cell International 2017:2057168.
3. Cellular mechano-environment regulates the mammary circadian clock. 2017 Nature Communications 30 (8):14287
4. Ageing in relation to skeletal muscle dysfunction: redox homeostasis to regulation of gene expression. 2016 Mammalian Genome 27 (7-8): 341-357.
5. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. 2014 Genes & Development 28 (6): 548-60.
6. Timed loaded standing in female chronic fatigue syndrome compared to other populations. 2015 Journal of Rehabilitation Research and Development 52(1): 21-29
7. Minimal footwear improves stability and physical function in middle-aged and older people compared to conventional shoes. 2020 Clinical Biomechanics 71: 139-145.

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