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

Abstract

Changes in the levels of O-linked N-acetylglucosamine (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.

O-linked N -acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence

“…In rodent models, O-GlcNAc levels increase in multiple aged tissues (62). However, the molecular basis of the function of OGT in aging has not been clearly elucidated.…”

O-GlcNAcylation of AMPA Receptor GluA2 Is Associated with a Novel Form of Long-Term Depression at Hippocampal Synapses

“…Mounting evidence shows a causal relationship between perturbations in O-GlcNAcylation and heart disease, cancer, AD, and diabetes (Chou et al, 1995;Love and Hanover, 2005;Liu et al, 2006;Dias and Hart, 2007;Fülöp et al, 2008), although the cellular mechanisms are far from understood. In contrast, recent studies suggest O-GlcNAcylation may be an endogenous, rapidly activated stress survival response (Zachara et al, 2004;Liu et al, 2006).…”

“…Assays were performed as previously described (Gupta et al, 2010). Rats were placed in a test box for 9 min.…”

Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent

“…The majority of studies focusing on the role of O-GlcNAc in regulating cellular function have been in the context of chronic diseases including cancer, age-related diseases, diabetes, and diabetic complications (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). However, in 2004 Zachara et al (15) demonstrated for the first time that there was an acute increase in cellular O-GlcNAc levels in response to a range of stress stimuli and importantly that inhibition of this response increased cell death and conversely that augmenting this response increased tolerance of cells to stress.…”