# The role of UBR5 in skeletal muscle atrophy and regrowth

> **NIH NIH R03** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $170,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10868891
- **Project number:** 1R03AR083980-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** David C Hughes
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,500
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868891

## Citation

> US National Institutes of Health, RePORTER application 10868891, The role of UBR5 in skeletal muscle atrophy and regrowth (1R03AR083980-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868891. Licensed CC0.

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