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The role of exercise mimetics on proteostasis function and dysfunction in skeletal muscle
Secondary Supervisor(s): Dr Yu-Chiang Lai
University of Registration: Coventry University
BBSRC Research Themes: Integrated Understanding of Health (Ageing)
Project Outline
Skeletal muscle accounts for approximately 60% of total body mass and is pivotal for maintaining whole-body health [1]. Physical inactivity, disuse, or ageing lead to proteostasis dysfunction, resulting in a decline in skeletal muscle mass. Multiple pathways regulate proteostasis to ensure the maintenance of protein turnover and quality [2]. However, despite the gradual loss in skeletal muscle mass across the life course, there is limited knowledge on the pathways that regulate protein breakdown and its role in proteostasis dysfunction [3].
Maintaining an active lifestyle, through regular exercise, can attenuate the decline in muscle mass and improve the quality of life by promoting positive cellular, tissue and whole-body adaptions [4]. Exercise mimetics, such as electrical pulse stimulation (EPS)), provide insight into molecular adaptions of skeletal muscle at the cellular level [5]. Recent advances in the mechanisms that regulate exercise-induced protein degradation and its importance in maintaining proteostasis have been identified [3]; however, there remains gaps in the literature as to the role of exercise mimetics play in the regulation of protein breakdown in skeletal muscle.
Aim
The aim of this project is to elucidate the cellular mechanisms underlying skeletal muscle proteostasis dysfunction and investigate how exercise mimetics can mitigate this dysfunction.
Objective 1: To establish the factors implicated in the dysregulation of skeletal muscle proteostasis.
Objective 2: To determine the exercise mimetic induced proteostasis response in human skeletal muscle cells.
Objective 3: To interrogate the molecular mechanism of exercise induced reversal of muscle breakdown in cellular ageing of skeletal muscle cells exposed to exercise mimetics.
Methods
The project will utilise the molecular tools established by the Lai group (University of Birmingham) and EPS methods established by the Turner group (Coventry University) to understand the mechanisms that underpin the skeletal muscle proteostasis in response to exercise mimetics. The project will generate a holistic picture using advanced analytical approaches (e.g. RNA-Sequencing, Proteomics, Immunoblotting and Immunohistochemistry) to determine the mechanisms which regulate protein degradation and the response to exercise mimetics.
References
1. McLeod, M., et al., Live strong and prosper: the importance of skeletal muscle strength for healthy ageing. Biogerontology, 2016. 17(3): p. 497-510.
2. Lemmer, I.L., et al., A guide to understanding endoplasmic reticulum stress in metabolic disorders. Mol Metab, 2021. 47: p. 101169.
3. Nishimura, Y., et al., Recent advances in measuring and understanding the regulation of exercise-mediated protein degradation in skeletal muscle. Am J Physiol Cell Physiol, 2021. 321(2): p. C276-C287.
4. Egan, B. and A.P. Sharples, Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiol Rev, 2023. 103(3): p. 2057-2170.
5. Mengeste, A.M., et al., Insight Into the Metabolic Adaptations of Electrically Pulse-Stimulated Human Myotubes Using Global Analysis of the Transcriptome and Proteome. Front Physiol, 2022. 13: p. 928195.
