# Mechanisms of Protein-Energy-Wasting in chronic kidney disease

> **NIH NIH R56** · BAYLOR COLLEGE OF MEDICINE · 2020 · $352,000

## Abstract

Project Abstract
 Skeletal muscle atrophy is a debilitating response to systemic diseases, including diabetes,
cancer, and chronic kidney disease (CKD). Under these conditions, muscle protein loss occurs,
which contributes substantially to morbidity and mortality. Therefore, maintenance of skeletal
muscle function is one of the top health priorities reported by patients living with catabolic
diseases. Although significant progress has been made in this area during recent decades, the
signaling pathways that regulate muscle proteolysis and the development of therapeutic
strategies treating muscle atrophy are still being investigated.
 We plan to identify the CRL4ACRBN ubiquitin E3 ligase as a novel catabolic mediator
promoting muscle protein degradation. Our Preliminary Results demonstrate that the CRL4ACRBN
E3 ligase was activated in muscle of CKD mice. Disruption of CRL4ACRBN specifically in muscle
significantly inhibits CKD-induced muscle atrophy. This beneficial response was associated with
suppressed atrogenes expression and reduced oxidative stress. Using the tandem-affinity
purification of ubiquitinated proteins following quantitative mass spectrometry analysis, we
identified two proteins, ovarian tumor (OTU) deubiquitinase 7B (OTUD7B) and peroxiredoxin-5
(PRDX5), that represent potential targets of the CRL4ACRBN E3 ligase. OTUD7B is a
deubiquitinating enzyme that is involved in the regulation of mechanistic target of rapamycin
complex 2 (mTORC2) and PRDX5 reportedly suppresses mitochondrial-associated oxidative
stress. In cultured human skeletal muscle cells, pomalidomide, a CRL4ACRBN inhibitor, blocked
cytokines-induced decline in OTUD7B and PRDX5 and this response was associated with
impeded atrogenes expression and proteolysis. Thus, we hypothesize that the activation of
CRL4ACRBN accelerates the degradation of OTUD7B and PRDX5, resulting in suppression of
anabolic signaling and enhanced oxidative stress. Conversely, the genomic or pharmacological
inhibition of CRL4ACRBN should improve anabolic signaling and prevent oxidative stress,
consequently, limiting the development of muscle atrophy under catabolic conditions. To test our
hypothesis, we plan to use human skeletal muscle cells and a humanized mouse model to
pursue three Specific Aims:
Specific Aim 1: To identify how the CRL4ACRBN E3 ligase is activated during catabolic states.
Specific Aim 2: To identify the mechanisms by which the disruption of CRL4ACRBN E3 ligase can
prevent muscle atrophy.
Specific Aim 3: To determine whether the pharmacologic inhibition of CRL4ACRBN E3 ligase can
reverse muscle atrophy under catabolic conditions.
 The results of these studies could identify novel pathways involved in the pathogenesis of
muscle atrophy and provide a feasible therapeutic strategy to combat muscle atrophy.

## Key facts

- **NIH application ID:** 10239946
- **Project number:** 2R56AR063686-06A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zhaoyong Hu
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,000
- **Award type:** 2
- **Project period:** 2020-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239946

## Citation

> US National Institutes of Health, RePORTER application 10239946, Mechanisms of Protein-Energy-Wasting in chronic kidney disease (2R56AR063686-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10239946. Licensed CC0.

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