# Exploring regulatory mechanisms of glyoxalase-1

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $195,000

## Abstract

PROJECT ABSTRACT
Methylglyoxal (MG) is a potent intracellular glycating agent that forms advanced glycation endproducts. Formed
spontaneously from 3-carbon glycolytic intermediates, MG rapidly glycates proteins and nucleotides, damages
mitochondria and directly increases reactive oxygen species production; thus inducing a pro-oxidant state and
senescent-like condition. MG and the related glyoxalase enzymatic defense system are emerging as critical
players in aging and age-related disease processes. Under physiologic conditions MG is rapidly detoxified by
glyoxalase 1 (GLO1). However, when GLO1 is attenuated, MG flux is increased and MG-modified proteins
accumulate (termed dicarbonyl stress), both within and outside the cell. Dicarbonyl stress promotes glucose
intolerance, oxidative stress and inflammation. The mechanisms regulating GLO1 protein stability and enzymatic
activity in skeletal muscle tissue, a tissue critical to glucose metabolism, are not well studied and there is a critical
need to understand the functional consequences of reduced GLO1 in the context of obesity, aging and age-
related disease. GLO1 is critical to cellular function and subject to numerous posttranslational modifications
(PTMs) that regulate GLO1 protein stability and activity. Our objective is to establish robust translational models
to delineate the mechanisms by which GLO1 is regulated to better understand the functional consequences of
attenuated GLO1. The generation of new, state-of-the-art translational models will help to accelerate the
understanding of GLO1 attenuation and dicarbonyl stress and the implications for skeletal muscle health across
both the life-span and health-span. We aim to establish the functional relevance of both GLO1 loss and the
impact of PTMs of GLO1 in human myotubes. Our approach is to attenuate GLO1 and mutate critical amino acid
residues using CRISPR gene editing technology, coupled with measures of dicarbonyl stress. We expect to
identify a novel, muscle specific mechanism of GLO1 dysregulation and methylglyoxal-mediated damage. The
successful completion of this work will have an important positive impact on advancing the understanding, and
provide potential therapeutic targets, to maintain skeletal muscle function with aging and age-related disease.

## Key facts

- **NIH application ID:** 10828440
- **Project number:** 5R21AG081916-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JACOB M HAUS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2023-04-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828440

## Citation

> US National Institutes of Health, RePORTER application 10828440, Exploring regulatory mechanisms of glyoxalase-1 (5R21AG081916-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10828440. Licensed CC0.

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