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Principal Investigator: JACOB M HAUS
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $195,000
Funding agency: National Institute on Aging
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.
Terms: <2-oxo-propanal><21+ years old><Acceleration><Acetylation><Acetylformaldehyde><Active Oxygen><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Advanced Glycation End Products><Advanced Glycosylation End Products><Alanine><Amino Acids><Antioxidants><Attenuated><Body Tissues><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Carbon><Cas nuclease technology><Cell Body><Cell Culture Techniques><Cell Function><Cell Line><Cell Physiology><Cell Process><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Coupled><Data><Deacetylase><Deacetylation><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Enzyme Gene><Enzymes><Gene Copy Number><Gene Dosage><Generations><Genetics-Mutagenesis><Glucose Intolerance><Glyoxalase I><Health><Heterozygote><Human><Impairment><Inflammation><Inflammatory><Insulin Resistance><Intermediary Metabolism><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knockout><Knowledge><L-Lysine><L-Threonine><Lactoyl Glutathione Lyase><Lactoylglutathione Lyase><Leanness><Lysine><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Drug Detoxications><Metabolic Processes><Metabolism><Metabolism of Toxic Agents><Methylglyoxal><Methylglyoxalase><Mitochondria><Modeling><Modern Man><Modification><Muscle><Muscle Fibers><Muscle Tissue><Muscle function><Mutagenesis><Mutagenesis Molecular Biology><Mutate><Myotubes><NADH><NIDDM><NMN pyrophosphorylase><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nucleotides><Obesity><Organ><Overnutrition><Oxidative Stress><Oxygen Radicals><Peptides><Phenotype><Phosphorylation><Phosphorylation Inhibition><Physiologic><Physiological><Polyubiquitination><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modification Site><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modification Site><Posttranslational Modifications><Posttranslational Protein Processing><Pro-Oxidants><Process><Production><Protein Modification><Protein Phosphorylation><Proteins><Proteomics><Pyruvaldehyde><Pyruvic Aldehyde><Reactive Oxygen Species><Regulation><Rhabdomyocyte><Role><SIRT1><SIRT1 gene><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Proteins><Sirtuin 1><Sirtuins><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Strains Cell Lines><Stress><Subcellular Process><System><T2 DM><T2D><T2DM><Thesaurismosis><Thinness><Threonine><Tissues><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Voluntary Muscle><Work><adduct><adiposity><adult adiposity><adult obesity><adult onset diabetes><adult youth><adulthood><adults with obesity><advanced glycation endproduct><advanced glycosylation endproduct><age associated disease><age associated disorder><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age related human disease><age-related disease><age-related disorder><age-related impairment><aging associated><aging related><aminoacid><attenuate><attenuates><attenuation><cell culture><cell cultures><corpulence><cultured cell line><detoxification><functional outcomes><gain of function><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene-editing toolkit><genome editing><genomic editing><glucose metabolism><glycation><glyoxalase><health-span><healthspan><healthy life span><heterozygosity><in silico><in vitro Model><inhibitor><insulin resistant><insulin tolerance><ketosis resistant diabetes><knock-down><knockdown><life span><lifespan><loss of function><maturity onset diabetes><metabolism disorder><mitochondrial><muscular><mutant><nicotinamide phosphoribosyltransferase><nicotinamide ribonucleoside><nicotinamide ribose><nicotinamide riboside><nicotinamide-beta-riboside><non-enzymatic glycosylation><nonenzymatic glycosylation><novel><obesigenic><obesogenic><preservation><senescence><senescent><skeletal muscle metabolism><skeletal muscle protein metabolism><social role><stressor><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><translational model><type 2 DM><type II DM><type two diabetes><young adult><young adulthood>