Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: A preliminary study

doi:10.1016/j.exger.2012.11.011

Experimental Gerontology

Volume 48, Issue 2, February 2013, Pages 136-139

https://doi.org/10.1016/j.exger.2012.11.011 Get rights and content

Abstract

Regular exercise improves learning and memory, including during aging process. Interestingly, the imbalance of epigenetic mechanisms has been linked to age-related cognitive deficits. However, studies about epigenetic alterations after exercise during the aging process are rare. In this preliminary study we investigated the effect of aging and exercise on DNA methyltransferases (DNMT1 and DNMT3b) and H3-K9 methylation levels in hippocampus from 3 and 20-months aged Wistar rats. The animals were submitted to two exercise protocols: single session or chronic treadmill protocol. DNMT1 and H3-K9 methylation levels were decreased in hippocampus from aged rats. The single exercise session decreased both DNMT3b and DNMT1 levels in young adult rats, without any effect in the aged group. Both exercise protocols reduced H3-K9 methylation levels in young adult rats, while the single session reversed the changes on H3-K9 methylation levels induced by aging. Together, these results suggest that an imbalance on DNMTs and H3-K9 methylation levels might be linked to the brain aging process and that the outcome to exercise seems to vary through lifespan.

Introduction

Recently, epigenetic mechanisms have been linked to normal aging-related changes in the brain, as well as neuropsychiatric and neurodegenerative diseases (Saha and Pahan, 2006). Epigenetic typically involves modifications in the micro and macrostructure of chromatin, DNA and nuclear proteins, particularly histones, which can modulate the transcriptional machinery and allow long lasting modifications in the genome. DNA and histone methylation, in addition to histone acetylation, are the most extensively studied post-translational modifications, which can influence gene transcription (Kouzarides, 2007).

The histones can be methylated on either lysine (K) or arginine (R)-residues by histone methyltransferases. Site-specific methylation of amino acid residues can condensate or relax the chromatin structure, such as mono-methylation of histone H3 at K9 (H3-K9) is associated to transcriptional activation, whereas transcriptionally silent regions contain di- and tri-methylation of H3-K9 (Gupta et al., 2010). The impact of aging process and exercise on H3-K9 methylation is poorly exploited. While, DNA methylation is catalyzed by a group of enzymes called DNA methyltransferases (DNMTs), DNMT1, DNMT2, DNMT3a, and DNMT3b that transfer the methyl group from the donor S-adenosylmethionine (SAM) to 5′ position of the cytosine pyramidal ring. This process usually represses the gene transcription. DNMT1 is primarily involved in maintenance of DNA methylation after replication, while DNMT3a and DNMT3b are particularly important for de novo methylation (Reik et al., 1999). It has been described a genome-wide tendency to DNA hypomethylation in multiple vertebrate organs during aging process (Richardson, 2002, Wilson et al., 1987). In addition, the age-related global hypomethylation is related to DNMT1 deficits in senescent human fibroblasts (Lopatina et al., 2002). However, studies reporting DNMT content in the brain during aging process are lacking.

Interestingly, epigenetic mechanisms have been linked to the age-related cognitive decline, since histone deacetylase (HDAC) inhibitors have been shown to improve memory in aged rodents (Levenson and Sweatt, 2005, Reolon et al., 2011). Accordantly, some evidences demonstrated that exercise ameliorates aging-related cognitive function in rodents (Pietrelli et al., 2012, Radak et al., 2001), in addition, recent findings have demonstrated that the exercise was able to modulate the histone acetylation status, enhancing transcription of genes related to brain function (Elsner et al., 2011, Gomez-Pinilla et al., 2011).

Considering that exercise restores the age-related memory deficits and epigenetic mechanisms which may be related to protective effects of exercise, it is crucial to assess the modulation of exercise on epigenetic parameters in the normal aging process. Therefore, the aim of this investigation was to study the effect of aging and two treadmill exercise protocols, single session of treadmill or chronic treadmill protocol on methylation parameters, specifically, DNA methyltransferases 1 and 3b (DNMT1and DNMT3b) and histone H3 lysine 9 (H3-K9) methylation levels.

Section snippets

Animals and training

Male Wistar rats of different ages, 3 and 20-months-old were used. The animals were maintained under standard conditions (12-h light/dark, 22 ± 2 °C) with food and water ad libitum. The NIH “Guide for the Care and Use of Laboratory Animals” (No. 80-23, revised 1996) was followed in all experiments. The Local Ethics Committee (CEUA/UFRGS) approved all handling and experimental conditions (nr. 21449).

Rats were randomly divided into sedentary (SED) or exercised group (EXE). The exercise training

Aging process reduces epigenetic markers in rat hippocampus

Firstly, we evaluated the effect of the aging process on histone methylation levels. 20-months-old rats hippocampi displayed lower histone H3-K9 methylation levels (about 50%) compared to the young adult group (Fig. 1; p = 0.0002). It was also observed that DNMT1 levels were significantly diminished (about 25%) in the aged group (Fig. 1; p = 0.009). The level of DNMT3b enzyme was not modified by age.

Exercise decreased DNMT3b and DNMT1 levels in hippocampi from young adult rats

The DNMT3b levels after single session of exercise are illustrated in Fig. 2A. Three-way ANOVA

Discussion

We described here that aged hippocampus has diminished DNMT1 and H3-K9 methylation levels. Our data corroborates to those obtained by Lopatina and et al. (2002), demonstrating decreases on DNMT1 activity in senescent human fibroblasts. These findings can be related to genome-wide tendency to DNA hypomethylation during aging process (Richardson, 2002, Wilson et al., 1987). The relevance of our finding is not currently known, although we can suggest that might reflect age-related global patterns

Conclusions

The present findings bring new insights into the effects of aging process and exercise on epigenetic modulation in rat hippocampus. Summarizing, our results support the hypothesis that an imbalance on epigenetic mechanisms, specifically DNMTs and H3-K9 methylation levels, are linked to brain aging process that might ultimately lead to age-related dysfunctions. Furthermore, exercise induced age-dependent changes on methylation markers, providing evidence that the epigenetic mechanisms in

Acknowledgments

This work was supported by the Brazilian funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq (Dr. I.R. Siqueira; V.R. Elsner; C.F. Spindler); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES (K. Bertoldi; G.A. Lovatel; F. Moysés); Programa Institucional de Bolsas de Iniciação Cientifica-PIBIC CNPq-UFRGS (L.R. Cechinel). Dr. A.R. Muotri was supported from the National Institutes of Health through the NIH Director's New Innovator Award Program,

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Short reportExercise induces age-dependent changes on epigenetic parameters in rat hippocampus: A preliminary study

Abstract

Introduction

Section snippets

Animals and training

Aging process reduces epigenetic markers in rat hippocampus

Exercise decreased DNMT3b and DNMT1 levels in hippocampi from young adult rats

Discussion

Conclusions

Acknowledgments

Epilepsy Res.

Psychoneuroendocrinology

Neuroscience

J. Nutr.

Cell

Neuroscience

Neurochem. Int.

Behav. Brain Res.

J. Nutr.

J. Biol. Chem.

Determination of metabolic and heart rate responses of rats to treadmill exercise

J. Appl. Physiol.

Short report
Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: A preliminary study