Thursday, May 9, 2024
5/9/2024
Project Summary/Abstract Skeletal muscle atrophy occurs as a consequence of many chronic diseases and conditions such as disuse. Protein turnover is important in maintaining skeletal muscle health and contributes to the process of atrophy and growth. Protein degradation is central to the process of muscle atrophy, for which the E3 ubiquitin ligases are critical in targeting specific proteins for degradation. The role of many E3 ubiquitin ligases in muscle are unknown and specific substrates have yet to be identified. The overall objective of this proposal is to determine the role of the conserved E3 ligase, Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5), in skeletal muscle atrophy and growth. We have previously observed UBR5 to be increased in multiple mammalian models of growth and recovery from atrophy. My central hypothesis is that UBR5 is critical for protein turnover and maintaining muscle mass via mTORC1 regulation. Robust preliminary data supports this hypothesis: 1) Loss of UBR5 induces skeletal muscle atrophy and chronic hyperactivation of mTORC1 activity, and 2) Genetic activation of protein synthesis increases UBR5 and induces muscle growth. I propose two specific aims: Aim 1 will define the importance of UBR5 in the process of atrophy and growth. I will address this aim using a muscle knockdown of UBR5 in a model of nerve crush to look at the loss of muscle mass and the ability for muscle to recover following a period of disuse. Protein turnover will be assessed via stable isotope labelling to determine rates of protein synthesis and breakdown under atrophy and growth conditions with UBR5 suppression. Aim 2 will seek to understand the relationship between UBR5 and protein synthesis via Akt/mTORC1 signaling and how this potential interaction influences overall skeletal muscle health. I will address this aim using a combined approach of UBR5 or Akt gene manipulation with and without rapamycin treatment (an mTORC1 inhibitor). With the completion of these pilot studies, I expect to identify novel mechanisms for understanding the process of muscle atrophy and growth. This will allow us to explore new therapeutic strategies for improving an individual’s quality of life where muscle wasting is present and improve recovery.
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