The goal of the lab is to identify molecular mechanisms that contribute to the development of dysfunction in aging skeletal muscle and understand how protein quality control via degradation and post-translational modifications (e.g. ubiquitination and acetylation) contribute to the dysfunction.
Post-translational modifications are an important component of proteostasis because they allow the proteome to respond quickly to stress events, as these modifications (e.g., ubiquitination, acetylation) regulate protein function and degradation. The conserved UBR-box family of E3 ubiquitin ligases (e.g., UBR2, UBR5) are essential components of protein quality control that target substrates for proteasomal degradation. As the UBR-box E3 ubiquitin ligases are part of the ubiquitin proteasome system (UPS) and the N-degron pathway, they have the capacity to recognize ubiquitin and acetyl motifs on destabilized protein substrates which subsequently affects the protein half-life. The UPS and N-degron pathway are poorly characterized in skeletal muscle and little is known how they contribute towards proteostasis and respond to cellular stress under aging, atrophy and other age-related diseases. Thus, investigating these systems will provide an opportunity for therapeutic approaches to be developed around protein clearance and alleviating proteotoxic stress, with the goal of improving skeletal muscle function and health in disease and aging.
Figure 1. Overview of experimental approaches used where UBR-box E3 ubiquitin ligases have been identified in skeletal muscle (reference: Hughes DC & Bodine SC. Exercise and Sport Sciences Reviews 2025).
Project 1. The role of protein quality control in age related muscle loss. E3 ubiquitin ligases are important components of the ubiquitin proteasome system and provide a critical step in selecting protein substrates for ubiquitination and potential proteolytic or non-proteolytic fates. Relatively few E3 ubiquitin ligases have been studied in the context of the aging process and skeletal muscle function. We have identified UBR5 to be critical in skeletal muscle health with biochemical sex differences being observed in rodent models with UBR5 knockdown. Our current studies are focused on understanding degradation signals in protein turnover and how proteolytic pathways change with age.
Project 2. The role of nuclear hormone receptors in sexual dimorphism, exercise, and atrophy. Nuclear (hormone) receptors are critical in responding to signals such as nutrients, exercise and hormonal status leading to the activation of specific gene programs. However, there is limited knowledge on how these nuclear receptors are regulated. Our current studies are focused on how degradation/turnover of nuclear receptors might play a role in skeletal muscle plasticity under different stimuli such as, aging, disease and exercise.