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Aging leads to increased levels of protein O-linked N-acetylglucosamine in heart, aorta, brain and skeletal muscle in Brown-Norway rats

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Abstract

Changes in the levels of O-linked N-acetyl-glucosamine (O-GlcNAc) on nucleocytoplasmic protein have been associated with a number of age-related diseases such as Alzheimer’s and diabetes; however, there is relatively little information regarding the impact of age on tissue O-GlcNAc levels. Therefore, the goal of this study was to determine whether senescence was associated with alterations in O-GlcNAc in heart, aorta, brain and skeletal muscle and if so whether there were also changes in the expression of enzymes critical in regulating O-GlcNAc levels, namely, O-GlcNAc transferase (OGT), O-GlcNAcase and glutamine:fructose-6-phosphate amidotransferase (GFAT). Tissues were harvested from 5- and 24-month old Brown-Norway rats; UDP-GlcNAc, a precursor of O-GlcNAc was assessed by HPLC, O-GlcNAc and OGT levels were assessed by immunoblot analysis and GFAT1/2, OGT, O-GlcNAcase mRNA levels were determined by RT-PCR. In the 24-month old animals serum insulin and triglyceride levels were significantly increased compared to the 5-month old group; however, glucose levels were unchanged. Protein O-GlcNAc levels were significantly increased with age (30–107%) in all tissues examined; however, paradoxically the expression of OGT, which catalyzes O-GlcNAc formation, was decreased by ∼30% in the heart, aorta and brain. In the heart increased O-GlcNAc was associated with increased UDP-GlcNAc levels and elevated GFAT mRNA while in other tissues we found no difference in UDP-GlcNAc or GFAT mRNA levels. These results demonstrate that senescence is associated with increased O-GlcNAc levels in multiple tissues and support the notion that dysregulation of pathways leading to O-GlcNAc formation may play an important role in the development of age-related diseases.

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Abbreviations

AD:

Alzheimer disease

AP:

Chlatrin assembly protein

EC:

Excitation-contraction coupling

eNOS:

Endothelial nitrogen oxide synthase

FFA:

Free fatty acid

GFAT:

Glutamine: fructose-6-phosphate amidotransferase

GLUT:

Glucose transporter

GSK:

Glycogen synthase kinase

HBP:

Hexosamine biosynthesis pathway

HDL:

High density lipoprotein

IRS:

Insulin receptor substrate

O-GlcNAc:

O-linked N-acetylglucosamine

OGA:

N-acetylglycosidase, O-GlcNAc-ase

OGT:

O-glucoronyl transferase, O-GlcNAc transferase

PCA:

Perchloric acid

PUGNAc:

O-(2-Acetamido-2-deoxy-d-glucopyranosylidene)amino N-phenyl carbamate

STZ:

Streptozotocin

UDP-GalNAc:

Uridine diphospho-N-acetyl-galactosamine

UDP-GlcNAc:

Uridine diphospho-N-acetyl-glucosamine

UDP-HexNAc:

Uridine diphospho-N-acetyl-hexosamine

ZDF:

Zucker diabetic fatty

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Acknowledgements

This work was supported by grants from the NHLBI HL-076175 (RBM); HL-67464 and HL079364 (JCC) and HL-077100.

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Authors and Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0005, USA

    Norbert Fülöp, Wenguang Feng, Dongqi Xing, Kai He, Charlye A. Brocks, Andrew P. Miller & John C. Chatham

  2. Department of Cell Biology, MCLM 684, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    László G. Nőt, Richard B. Marchase & John C. Chatham

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  1. Norbert Fülöp
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  2. Wenguang Feng
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Correspondence to John C. Chatham.

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Fülöp, N., Feng, W., Xing, D. et al. Aging leads to increased levels of protein O-linked N-acetylglucosamine in heart, aorta, brain and skeletal muscle in Brown-Norway rats. Biogerontology 9, 139–151 (2008). https://doi.org/10.1007/s10522-007-9123-5

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