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Review
, 80, 443-456

Physical Exercise as an Epigenetic Modulator of Brain Plasticity and Cognition

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Review

Physical Exercise as an Epigenetic Modulator of Brain Plasticity and Cognition

Jansen Fernandes et al. Neurosci Biobehav Rev.

Abstract

A large amount of evidence has demonstrated the power of exercise to support cognitive function, the effects of which can last for considerable time. An emerging line of scientific evidence indicates that the effects of exercise are longer lasting than previously thought up to the point to affect future generations. The action of exercise on epigenetic regulation of gene expression seem central to building an "epigenetic memory" to influence long-term brain function and behavior. In this review article, we discuss new developments in the epigenetic field connecting exercise with changes in cognitive function, including DNA methylation, histone modifications and microRNAs (miRNAs). The understanding of how exercise promotes long-term cognitive effects is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

Keywords: Brain; DNA methylation; Epigenetics; Exercise; Histones; Memory; miRNAs.

Figures

Figure 1
Figure 1
Dynamic regulation of DNA methylation and histone modifications. (A) Nucleosome, the basic repeat element of chromatin, consists of 147bp of DNA wrapped around an octamer of four core histone proteins (H2A, H2B, H3 and H4) compacted by a linker histone. DNA methylation is related to repressed transcription and involves the covalent addition of a methyl group to the 5-carbon of cytosine bases [5-methylcytosine (5mC)] located in CpG dinucleotides by DNMTs. Conversely, active DNA demethylation can occur through mechanisms involving enzymes from Gadd45, TET and even DNMT families. (B) Chromatin-modifying enzymes regulate the addition and removal of histone modifications to establish an open or a silent transcriptional state. While HATs catalyze the addition of acetyl group, HDACs catalyze its removal. The histone tail is methylated by HMTs and demethylated by HDMs. PKs and PPs are responsible for the addition and removal of phosphate groups. (C) Chromatin can be found at an open (euchromatin) or a closed (heterochromatin) state according to the pattern of histone modifications. In general, euchromatin is characterized by hyperacetylated, hyperphosphorylated and specific histone methylation patterns related to active transcription whereas heterochromatin is featured by opposite post-translational modifications. Ac, acetyl group; CpG, cytosine-phosphate-guanine dinucleotides; DNMTs, DNA methyltransferases; Gadd45, growth arrest and DNA damage 45 proteins; HATs, histone acetyltransferases; HDACs, histone deacetylases; HDMs, histone demethylases; HMTs, histone methyltransferases; Me, methyl group; P, phosphate group; PKs, protein kinases; PPs, protein phosphatases; RNAPII, RNA polymerase II; TET, ten-eleven translocation proteins; TF, transcription factor.
Figure 2
Figure 2
miRNA biogenesis. miRNAs are initially transcribed into primary miRNA (pri-miRNA) that undergo processing by a microprocessor complex composed of Drosha and DiGeorge syndrome critical region 8 (DGCR8). The resulting precursor miRNAs (pre-miRNAs) are transported from the nucleus to the cytoplasm by exportin 5 (Exp5), in a guanosine triphosphate (GTP)-dependent manner, and further processed into its mature form by Dicer. The mature miRNA is then loaded into the RNA-induced silencing complex (RISC) to degrade or inhibit the translation of target mRNA. The miRNAs can be released in the blood inside exosomes or in association with RNA-binding proteins and lipoproteins to spread signals to cells located in the vicinity or in other parts of the organism.
Figure 3
Figure 3
Potential epigenetic mechanism through which exercise-induced Bdnf expression may enhance synaptic plasticity and cognition. Exercise-induced glutamate release stimulates NMDA-R and, consequently, the influx of Ca2+ in the postsynaptic neurons. Increases in Ca2+ levels trigger a wave of molecular events leading to the activation of CaMKII and MAPK/ERK/MSK signaling. CaMKII phosphorylates MeCP2 inducing its dissociation, along with other co-repressors (Sin3A and HDACs), from the promoter region of Bdnf gene. The effects of exercise on MeCP2 dissociation from Bdnf promoter may also involve the SIRT1-dependent deacetylation of MeCP2, given that the metabolic changes underlying SIRT1 activity and expression are directly modulated by exercise. Besides the phosphorylation of the transcription factor CREB, the activation of CAMKII and MAPK/ERK/MSK signaling induced by exercise phosphorylates some histone proteins and promotes the recruitment and activation of CBP, a HAT. Altogether, these alterations changes the configuration of chromatin to an open state allowing the transcription of Bdnf which, after translated, can bind to its receptor TrkB to engage a positive feedback loop underlying the positive effects of exercise on synaptic plasticity and cognitive abilities. Ac, acetyl group; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; Bdnf, brain-derived neurotrophic factor; CaMKII, Ca2+/Calmodulin-dependent kinase II; CBP, CREB-binding protein; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; Me, methyl group; MeCP2, methyl-CpG-binding protein 2; NAD+, nicotinamide adenine dinucleotide (oxidized); NADH, nicotinamide adenine dinucleotide (reduced); NMDA-R, N-methyl-D-aspartate receptor; P, phosphate group; Sin3a, paired amphipathic helix protein Sin3a; HDACs, histone deacetylases; SIRT1, sirtuin 1.

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