Impact of Physical Activity and Exercise on the Epigenome in Skeletal Muscle and Effects on Systemic Metabolism

Exercise and physical activity induces physiological responses in organisms, and adaptations in skeletal muscle, which is beneficial for maintaining health and preventing and/or treating most chronic diseases. These adaptations are mainly instigated by transcriptional responses that ensue in reaction to each individual exercise, either resistance or endurance. Consequently, changes in key metabolic, regulatory, and myogenic genes in skeletal muscle occur as both an early and late response to exercise, and these epigenetic modifications, which are influenced by environmental and genetic factors, trigger those alterations in the transcriptional responses. DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise, and mediating the exercise adaptations. Nevertheless, other alterations in the epigenetics markers, such as epitranscriptomics, modifications mediated by miRNAs, and lactylation as a novel epigenetic modification, are emerging as key events for gene transcription. Here, we provide an overview and update of the impact of exercise on epigenetic modifications, including the well-described DNA methylations and histone modifications, and the emerging modifications in the skeletal muscle. In addition, we describe the effects of exercise on epigenetic markers in other metabolic tissues; also, we provide information about how systemic metabolism or its metabolites influence epigenetic modifications in the skeletal muscle.

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Spontaneous HTLV-1 transcription is accompanied by distinct epigenetic changes in the 5′ and 3′ long terminal repeats

Wellcome Open Research ◽

10.12688/wellcomeopenres.14741.1 ◽

2018 ◽

Vol 3 ◽

pp. 105 ◽

Cited By ~ 1

Author(s):

Michi Miura ◽

Paola Miyazato ◽

Yorifumi Satou ◽

Yuetsu Tanaka ◽

Charles R.M. Bangham

Keyword(s):

Histone Modifications ◽

Insertion Site ◽

Rapid Change ◽

Epigenetic Modifications ◽

The Body ◽

Ctcf Binding ◽

Ctcf Binding Site ◽

Long Terminal Repeats ◽

Terminal Repeats ◽

The Impact

Background:The human retrovirus HTLV-1 inserts the viral complementary DNA of 9 kb into the host genome. Both plus- and minus-strands of the provirus are transcribed, respectively from the 5′ and 3′ long terminal repeats (LTR). Plus-strand expression is rapid and intense once activated, whereas the minus-strand is transcribed at a lower, more constant level. To identify how HTLV-1 transcription is regulated, we investigated the epigenetic modifications associated with the onset of spontaneous plus-strand expression and the potential impact of the host factor CTCF.Methods:Patient-derived peripheral blood mononuclear cells (PBMCs) and in vitro HTLV-1-infected T cell clones were examined. Cells were stained for the plus-strand-encoded viral protein Tax, and sorted into Tax+and Tax–populations. Chromatin immunoprecipitation and methylated DNA immunoprecipitation were performed to identify epigenetic modifications in the provirus. Bisulfite-treated DNA fragments from the HTLV-1 LTRs were sequenced. Single-molecule RNA-FISH was performed, targeting HTLV-1 transcripts, for the estimation of transcription kinetics. The CRISPR/Cas9 technique was applied to alter the CTCF-binding site in the provirus, to test the impact of CTCF on the epigenetic modifications.Results:Changes in the histone modifications H3K4me3, H3K9Ac and H3K27Ac were strongly correlated with plus-strand expression. DNA in the body of the provirus was largely methylated except for the pX and 3′ LTR regions, regardless of Tax expression. The plus-strand promoter was hypomethylated when Tax was expressed. Removal of CTCF had no discernible impact on the viral transcription or epigenetic modifications.Conclusions:The histone modifications H3K4me3, H3K9Ac and H3K27Ac are highly dynamic in the HTLV-1 provirus: they show rapid change with the onset of Tax expression, and are reversible. The HTLV-1 provirus has an intrinsic pattern of epigenetic modifications that is independent of both the provirus insertion site and the chromatin architectural protein CTCF which binds to the HTLV-1 provirus.

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Alterations in epigenetic modifications during oocyte growth in mice

Reproduction ◽

10.1530/rep-06-0025 ◽

2007 ◽

Vol 133 (1) ◽

pp. 85-94 ◽

Cited By ~ 140

Author(s):

Shun-ichiro Kageyama ◽

Honglin Liu ◽

Naoto Kaneko ◽

Masatoshi Ooga ◽

Masao Nagata ◽

...

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Epigenetic Modification ◽

Germinal Vesicle ◽

Epigenetic Modifications ◽

Condensed Chromatin ◽

Rt Pcr ◽

Oocyte Growth ◽

Lysine Residues ◽

Signal Intensities

During oocyte growth, chromatin structure is altered globally and gene expression is silenced. To investigate the involvement of epigenetic modifications in the regulation of these phenomena, changes in global DNA methylation and in various histone modifications, i.e. acetylation of H3K9, H3K18, H4K5, and H4K12, and methylation of H3K4 and H3K9, were examined during the growth of mouse oocytes. Immunocytochemical analysis revealed that the signal intensities of all these modifications increased during growth and that fully grown, germinal vesicle (GV)-stage oocytes showed the most modifications. Since acetylation of most of the lysine residues on histones and methylation of H3K4 are associated with active gene expression, the increased levels of these modifications do not seem to be associated with gene silencing in GV-stage oocytes. Given that there are two types of GV-stage oocytes with different chromatin configurations and transcriptional activities, the epigenetic modification statuses of these two types were compared. The levels of all the epigenetic modifications examined were higher in the SN(surrounded nucleolus)-type oocytes, in which highly condensed chromatin is concentrated in the area around the nucleolus and gene expression is silenced than in the NSN(not surrounded nucleolus)-type oocytes, in which less-condensed chromatin does not surround the nucleolus and gene expression is active. In addition, the expression levels of various enzymes that catalyze histone modifications were shown by RT-PCR to increase with oocyte growth. Taken together, the results show that all of the epigenetic modifications increased in a concerted manner during oocyte growth, and suggest that these increases are not associated with gene expression.

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The impact of diet and physical activity on skeletal muscle mass and strength in Caucasian women: implications for sarcopenia prevention

Proceedings of The Nutrition Society ◽

10.1017/s0029665115001767 ◽

2015 ◽

Vol 74 (OCE2) ◽

Cited By ~ 1

Author(s):

K. Shilland ◽

H. D. McCarthy

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Diet And Physical Activity ◽

Caucasian Women ◽

The Impact

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Using exercise training to understand control of skeletal muscle metabolism

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0356 ◽

2017 ◽

Vol 42 (1) ◽

pp. 108-110

Author(s):

Martin J. Gibala

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Exercise Training ◽

Metabolic Control ◽

Physical Training ◽

Muscle Metabolism ◽

Integrative Physiology ◽

Skeletal Muscle Metabolism ◽

Scientific Curiosity ◽

The Impact

Bengt Saltin believed that exercise was the unsurpassed tool to study human integrative physiology. He demonstrated this over the course of his career by employing physical training as a model to advance our understanding of skeletal muscle metabolic control and the impact of physical activity on performance and health. Bengt was also a pioneer in advocating the concept of exercise is medicine. His scientific curiosity was perhaps exceeded only by his generosity.

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The Influence of Physical Activity on the Bioactive Lipids Metabolism in Obesity-Induced Muscle Insulin Resistance

Biomolecules ◽

10.3390/biom10121665 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1665

Author(s):

Monika Imierska ◽

Adam Kurianiuk ◽

Agnieszka Błachnio-Zabielska

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Biologically Active ◽

Bioactive Lipids ◽

Glucose Levels ◽

Insulin Dependent ◽

Lipids Metabolism ◽

The Impact

High-fat diet consumption and lack of physical activity are important risk factors for metabolic disorders such as insulin resistance and cardiovascular diseases. Insulin resistance is a state of a weakened response of tissues such as skeletal muscle, adipose tissue, and liver to insulin, which causes an increase in blood glucose levels. This condition is the result of inhibition of the intracellular insulin signaling pathway. Skeletal muscle is an important insulin-sensitive tissue that accounts for about 80% of insulin-dependent glucose uptake. Although the exact mechanism by which insulin resistance is induced has not been thoroughly understood, it is known that insulin resistance is most commonly associated with obesity. Therefore, it is believed that lipids may play an important role in inducing insulin resistance. Among lipids, researchers’ attention is mainly focused on biologically active lipids: diacylglycerols (DAG) and ceramides. These lipids are able to regulate the activity of intracellular enzymes, including those involved in insulin signaling. Available data indicate that physical activity affects lipid metabolism and has a positive effect on insulin sensitivity in skeletal muscles. In this review, we have presented the current state of knowledge about the impact of physical activity on insulin resistance and metabolism of biologically active lipids.

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Epigenetic Modification of CFTR in Head and Neck Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9030734 ◽

2020 ◽

Vol 9 (3) ◽

pp. 734 ◽

Cited By ~ 3

Author(s):

Yonghwan Shin ◽

Minkyoung Kim ◽

Jonghwa Won ◽

Junchul Kim ◽

Seog Bae Oh ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Epigenetic Modification ◽

Expression Patterns ◽

Cpg Islands ◽

Epigenetic Modifications ◽

Patch Clamp Technique ◽

Normal Cells ◽

The Impact

Cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, is critical for secretion and absorption across diverse epithelia. Mutations or absence of CFTR result in pathogeneses, including cancer. While CFTR has been proposed as a tumor suppressing gene in tumors of the intestine, lung, and breast cancers, its effects in head and neck cancer (HNC) have yet to be investigated. This study aimed to define expression patterns and epigenetic modifications of CFTR in HNC. CFTR was expressed in normal but not in HNC cells and tissues. Treatment with 5-aza-2′-deoxycytidine (5-Aza-CdR) was associated with rescued expression of CFTR, whose function was confirmed by patch clamp technique. Further experiments demonstrated that CFTR CpG islands were hypermethylated in cancer cells and tissues and hypomethylated in normal cells and tissue. Our results suggest that CFTR epigenetic modifications are critical in both down-regulation and up-regulation of CFTR expression in HNC and normal cells respectively. We then investigated the impact of CFTR on expressions and functions of cancer-related genes. CFTR silencing was closely associated with changes to other cancer-related genes, suppressing apoptosis while enhancing proliferation, cell motility, and invasion in HNC. Our findings demonstrate that hypermethylation of CFTR CpG islands and CFTR deficiency is closely related to HNC.

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The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12139 ◽

2016 ◽

Vol 8 (2) ◽

pp. 213-228 ◽

Cited By ~ 54

Author(s):

Félix St-Jean-Pelletier ◽

Charlotte H Pion ◽

Jean-Philippe Leduc-Gaudet ◽

Nicolas Sgarioto ◽

Igor Zovilé ◽

...

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Intramyocellular Lipids ◽

Mitochondrial Content ◽

The Impact

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Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity

Nature Communications ◽

10.1038/s41467-019-13869-w ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 34

Author(s):

Nicolas J. Pillon ◽

Brendan M. Gabriel ◽

Lucile Dollet ◽

Jonathon A. B. Smith ◽

Laura Sardón Puig ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Molecular Mechanisms ◽

Meta Analysis ◽

Chronic Exercise ◽

Transcriptional Responses ◽

Pathway Analyses ◽

Response To Exercise ◽

Skeletal Muscle Adaptations

AbstractThe molecular mechanisms underlying the response to exercise and inactivity are not fully understood. We propose an innovative approach to profile the skeletal muscle transcriptome to exercise and inactivity using 66 published datasets. Data collected from human studies of aerobic and resistance exercise, including acute and chronic exercise training, were integrated using meta-analysis methods (www.metamex.eu). Here we use gene ontology and pathway analyses to reveal selective pathways activated by inactivity, aerobic versus resistance and acute versus chronic exercise training. We identify NR4A3 as one of the most exercise- and inactivity-responsive genes, and establish a role for this nuclear receptor in mediating the metabolic responses to exercise-like stimuli in vitro. The meta-analysis (MetaMEx) also highlights the differential response to exercise in individuals with metabolic impairments. MetaMEx provides the most extensive dataset of skeletal muscle transcriptional responses to different modes of exercise and an online interface to readily interrogate the database.

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Exercise induces a transient increase in transcription of the GLUT-4 gene in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.1993.265.6.c1597 ◽

1993 ◽

Vol 265 (6) ◽

pp. C1597-C1603 ◽

Cited By ~ 128

Author(s):

P. D. Neufer ◽

G. L. Dohm

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Protein Content ◽

Gene Transcription ◽

Training Session ◽

Transient Increase ◽

Initial Increase ◽

Control Mechanisms ◽

Glut 4 ◽

Response To Exercise

Endurance exercise training elicits an increase in mitochondrial density as well as GLUT-4 glucose transporter protein content in skeletal muscle. Corresponding increases in mRNA for respiratory enzymes and GLUT-4 indicate that pretranslational control mechanisms are involved in this adaptive process. To directly test whether transcription of the GLUT-4 gene is activated in response to exercise training, nuclei were isolated from red hindlimb skeletal muscle of rats after 1 wk of exercise training (8% grade, 32 m/min, 40 min, twice/day). Rats were killed either 30 min, 3 h, or 24 h after the last training session. GLUT-4 transcription, determined by nuclear run-on analysis, was unaltered after 30 min, increased by 1.8-fold after 3 h, but was no longer different from controls 24 h after exercise. A similar transient increase in GLUT-4 transcription was evident, but less pronounced (1.4-fold), in untrained rats after a single bout of exercise, suggesting that the postexercise induction in GLUT-4 gene transcription is enhanced by exercise training. GLUT-4 protein content was increased 1.7-fold after 1 wk of training in the absence of any corresponding change in GLUT-4 mRNA, providing evidence that the initial increase in GLUT-4 expression involves translational and/or posttranslational control mechanisms. These findings demonstrate that muscle GLUT-4 expression in response to exercise training is subject to both transcriptional and posttranscriptional regulation. We propose that the increase in GLUT-4 mRNA evident with extended periods of training may result from a shift to pretranslational control and is the cumulative effect of repeated postexercise transient increases in GLUT-4 gene transcription.

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