Dr Yu-Chiang Lai
Research Interests
Skeletal muscle loss is an underappreciated clinical disorder, not only reducing the quality of life but also contributing to morbidity and mortality. Loss of skeletal muscle is a cause of death in patients with cancers and several immune diseases, remarkably preservation of muscle mass increases survival. Currently, exercise is the only known countermeasure to slow this debilitating process, no approved therapeutic is available.
The loss of muscle mass and strength primarily results from excessive protein degradation, often accompanied by reduced protein synthesis, resulting in a negative net balance. It is known that the ubiquitin-regulated proteasomal and lysosomal systems are two major pathways responsible for muscle degradation. We thus aim to precisely dissect these signalling mechanisms.
Current projects are:
- Elucidate how MuRF1 (TRIM63) and MAFbx (FBXO32) contribute to muscle atrophy
- Identify novel ubiquitin E3 ligases, deubiquitylases (DUBs), and binding proteins in muscle atrophy
- The interplay of protein phosphorylation and ubiquitylation in muscle metabolism after exercise
We tackle these questions using a range of state-of-the-art techniques, including molecular & cellular engineering (such as CRISPR/Cas9 genetic editing), biochemistry, chemical biology, mass spectrometry and mouse genetics. Importantly, we are also exploring the physiological role of the ubiquitin system in skeletal muscle and therefore translating basic science to clinical research by employing human samples that are well established at the School of SportExR (University of Birmingham) and the MRC-ARUK Centre of Musculoskeletal and Ageing Research, joint with the University of Nottingham.
By 2050, the number of people over 60 years old will reach 2 billion worldwide (22% of the population). However, a longer life for many will mean more years of chronic diseases. Thus, only extending life is not enough and we need to find drugs that delay diseases of old age. A further aim of my research is therefore to identify which components of exercise-mediated signalling pathways are the most attractive drug target for the treatment of muscle loss and other age-related diseases.
Project Details
Dr Lai is the supervisor for the below project:
Investigating the ubiquitin network in exercising human skeletal muscle
Secondary Supervisor(s): Prof Gareth Wallis
University of Registration: University of Birmingham
BBSRC Research Themes:
- Understanding the Rules of Life (Systems Biology)
- Integrated Understanding of Health (Ageing, Diet and Health)
No longer accepting applications
Project Outline
We all knew that being physically active is beneficial for health, but until now we still do not have a clear understanding of what is happening deep in the body, or how the molecular communication changes that bring health. Since protein ubiquitylation is one of the key post-translational modifications affecting all most all biological function, our lab has focused on understanding how exercise improves muscle health and disease by researching protein ubiquitylation and ubiquitin signalling events. There are considerable research interests on ubiquitin-modifying enzymes (e.g. MuRF1, Atrogin1 and USP19) in muscle atrophy. However, information about which ubiqtuin E3 ligases/DUBs (deubiquitylases) account for the beneficial effects of exercise and what are their molecular partners and functions remains unclear. This PhD project will aim to fill the knowledge gaps by investigating the potential candidates that have been identified from our previous “Omic” databases (e.g. from ubiquitylome, phosphoproteome and RNAseq)
We have identified a list of DUBs, whose gene and/or protein expressions were changed in exercised human skeletal muscle. More interestingly, many of the potential targets were also occurring opposite changes in their protein/gene expression in aged skeletal muscle and/or disease-associated cardiomyocytes. To better understand their translational and functional roles, the student will first verify their gene and protein expression and study their localisation in exercised human skeletal muscles (Objective 1). The student will also aim to test whether genetic manipulation of these enzymes can alter the beneficial effects of exercise in myoblasts/cardiomyocytes and rodent tissues (Objective 2 and 3). Findings are expected to create new research avenues and accelerate the discovery of pharmaceutical targets for improving metabolic health and anti-ageing.
Our lab has been developing and collating a range of highly effective experimental tools for gaining mechanistic insights on the role of ubiquitin-modifying enzymes. For example, we established an E2 library screening platform and an effective workflow of the state-of the-art CRISPR/Cas9 technology for generating gene knockout and knock-in cells, which is crucial for this project. We also plan to use proteomic-based approaches, through collaboration with Dr Rahul Samant (Babraham Institute, Cambridge) to validate the candidate protein’s functional outputs and pathways in mouse or human muscle.
References
- Nishimura Y, Musa I, Holm L, Lai YC. (2021) Recent advances in measuring and understanding the regulation of exercise-mediated protein degradation in skeletal muscle. Am J Physiol Cell Physiol 321(2): C276-C287.
- Lord S, Lai YC. (2022) Exercise mediates ubiquitin signalling in human skeletal muscle. FASEB Bioadv. 4(6):402-407
Techniques
- Molecular cloning, gene transfection, and CRISPR/Cas9 knock out/in technology.
- Protein expression, purification, characterisation, and chemical modification.
- Biochemical and enzymatic assays.
- Scientific data analysis and bioinformatics.
Previous Projects
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