ORCID Profile
0000-0002-4074-7083
Current Organisation
Victoria University
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Epigenetics (incl. Genome Methylation and Epigenomics) | Exercise Physiology | Genetics | Preventive Medicine | Genomics
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Wiley
Date: 12-09-2023
Publisher: MDPI AG
Date: 26-04-2019
DOI: 10.3390/NU11050948
Abstract: According to the “developmental origins of health and disease” (DOHaD) concept, maternal obesity predisposes the offspring to non-communicable diseases in adulthood. While a preconceptional weight loss (WL) is recommended for obese women, its benefits on the offspring have been poorly addressed. We evaluated whether preconceptional WL was able to reverse the adverse effects of maternal obesity in a mouse model, exhibiting a modification of foetal growth and of the expression of genes encoding epigenetic modifiers in liver and placenta. We tracked metabolic and olfactory behavioural trajectories of offspring born to control, obese or WL mothers. After weaning, the offspring were either put on a control diet (CD) or a high-fat (HFD). After only few weeks of HFD, the offspring developed obesity, metabolic alterations and olfactory impairments, independently of maternal context. However, male offspring born to obese mother gained even more weight under HFD than their counterparts born to lean mothers. Preconceptional WL normalized the offspring metabolic phenotypes but had unexpected effects on olfactory performance: a reduction in olfactory sensitivity, along with a lack of fasting-induced, olfactory-based motivation. Our results confirm the benefits of maternal preconceptional WL for male offspring metabolic health but highlight some possible adverse outcomes on olfactory-based behaviours.
Publisher: Informa UK Limited
Date: 30-12-2021
DOI: 10.1080/17461391.2021.2011426
Abstract: Previous small-scale studies have shown an association between the
Publisher: Wiley
Date: 30-06-2021
DOI: 10.1002/JCSM.12741
Abstract: Knowledge of age‐related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. We conducted a large‐scale epigenome‐wide association study meta‐analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18–89 years old). We explored the genomic context of age‐related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age‐related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock ( ackages/release/bioc/html/MEAT.html ). We identified 6710 differentially methylated regions at a stringent false discovery rate .005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age‐related differential mRNA and protein expression. After adding a substantial number of s les from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 s les) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate. We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open‐access, user‐friendly, web‐based tool called MetaMeth ( sarah‐voisin.shinyapps.io/MetaMeth/ ).
Publisher: Springer Science and Business Media LLC
Date: 02-07-2020
DOI: 10.1186/S13148-020-00884-8
Abstract: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy in iduals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p adj. 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p raw = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippoc us of MDD patients compared with healthy controls ( p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 ( SHANK2 ) (p adj. = 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations at HACE1 and SHANK2 loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
Publisher: Public Library of Science (PLoS)
Date: 02-06-2016
Publisher: Frontiers Media SA
Date: 16-11-2018
Publisher: Elsevier BV
Date: 11-2019
Publisher: OMICS Publishing Group
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 22-04-2016
Publisher: Wiley
Date: 02-05-2023
DOI: 10.1111/ACEL.13859
Abstract: Exercise training prevents age‐related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late‐life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta‐analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle s les ( n = 3176). We show that: (1) in iduals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age‐related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2022
DOI: 10.1101/2022.12.27.522062
Abstract: Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle s les (n = 3,176). We show that: 1) in iduals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns towards a younger profile, and 3) muscle disuse “ages” the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
Publisher: Frontiers Media SA
Date: 05-02-2019
Publisher: Springer Science and Business Media LLC
Date: 11-2017
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2019
DOI: 10.1101/821009
Abstract: Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle s les, and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. To address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle s les from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation arrays (HM27, HM450 or HMEPIC). We also took advantage of the large number of s les to conduct an epigenome-wide association study (EWAS) of age-associated DNA methylation patterns in skeletal muscle. The newly developed clock uses 200 CpGs to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 CpGs of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets ( vs 13.1 years for the pan-tissue clock, p 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets ( vs ρ = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions (DMRs) with age in skeletal muscle at a False Discovery Rate 0.005. However, Gene Set Enrichment Analysis did not reveal any enrichment for Gene Ontologies. We have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an R package called MEAT available on Bioconductor to estimate epigenetic age in skeletal muscle s les. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.
Publisher: Elsevier BV
Date: 03-2021
Publisher: The Endocrine Society
Date: 09-2015
DOI: 10.1210/ME.2015-1077
Abstract: Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, Ilp6, and Ilp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.
Publisher: Impact Journals, LLC
Date: 03-01-2020
Publisher: Springer Science and Business Media LLC
Date: 23-01-2013
Publisher: The Endocrine Society
Date: 09-2015
DOI: 10.1210/JC.2015-2284
Abstract: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230–0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4% P = .026) and in two promoter-interacting enhancer regions of PER1 (+15% P = .036 +9% P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (−18% P = .033) and CRY1 (−22% P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L P = .011). Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2015
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
DOI: 10.1038/S41598-019-49042-Y
Abstract: Research in α-actinin-3 knockout mice suggests a novel role for α-actinin-3 as a mediator of cell signalling. We took advantage of naturally-occurring human “knockouts” (lacking α-actinin-3 protein) to investigate the consequences of α-actinin-3 deficiency on exercise-induced changes in mitochondrial-related genes and proteins, as well as endurance training adaptations. At baseline, we observed a compensatory increase of α-actinin-2 protein in ACTN3 XX (α-actinin-3 deficient n = 18) vs ACTN3 RR (expressing α-actinin-3 n = 19) participants but no differences between genotypes for markers of aerobic fitness or mitochondrial content and function. There was a main effect of genotype, without an interaction, for RCAN1-4 protein content (a marker of calcineurin activity). However, there was no effect of genotype on exercise-induced expression of genes associated with mitochondrial biogenesis, nor post-training physiological changes. In contrast to results in mice, loss of α-actinin-3 is not associated with higher baseline endurance-related phenotypes, or greater adaptations to endurance exercise training in humans.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-08-2018
Abstract: Simulated shift work uncovers potential tissue mechanisms for metabolic effects attributed to sleep loss and circadian disruption.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
DOI: 10.1519/JSC.0000000000001558
Abstract: Yang, R, Shen, X, Wang, Y, Voisin, S, Cai, G, Fu, Y, Xu, W, Eynon, N, Bishop, DJ, and Yan, X. ACTN3 R577X gene variant is associated with muscle-related phenotypes in elite Chinese sprint ower athletes. J Strength Cond Res 31(4): 1107–1115, 2017—The ACTN3 R577X polymorphism (rs1815739) has been shown to influence athletic performance. The aim of this study was to investigate the prevalence of this polymorphism in elite Chinese track and field athletes, and to explore its effects on athletes' level of competition and lower-extremity power. We compared the ACTN3 R577X genotypes and allele frequencies in 59 elite sprint ower athletes, 44 elite endurance athletes, and 50 healthy controls from Chinese Han origin. We then subcategorized the athletes into international level and national level and investigated the effects of ACTN3 genotype on lower-extremity power. Genotype distribution of the sprint ower athletes was significantly different from endurance athletes ( p = 0.001) and controls ( p 0.001). The frequency of the RR genotype was significantly higher in international-level than that in the national-level sprint ower athletes ( p = 0.004), with no international-level sprint ower athletes with XX genotype. The best standing long jump and standing vertical jump results of sprint ower athletes were better in the RR than those in the RX + XX genotypes ( p = 0.004 and p = 0.001, respectively). In conclusion, the ACTN3 R577X polymorphism influences the level of competition and lower-extremity power of elite Chinese sprint ower athletes. Including relevant phenotypes such as muscle performance in future studies is important to further understand the effects of gene variants on elite athletic performance.
Publisher: Informa UK Limited
Date: 27-03-2023
DOI: 10.1080/17461391.2022.2048894
Abstract: Multiple statistical methods have been proposed to estimate in idual responses to exercise training yet, the evaluation of these methods is lacking. We compared five of these methods including the following: the use of a control group, a control period, repeated testing during an intervention, a reliability trial and a repeated intervention. Apparently healthy males from the Gene SMART study completed a 4-week control period, 4 weeks of High-Intensity Interval Training (HIIT), >1 year of washout, and then subsequently repeated the same 4 weeks of HIIT, followed by an additional 8 weeks of HIIT. Aerobic fitness measurements were measured in duplicates at each time point. We found that the control group and control period were not intended to measure the degree to which in iduals responded to training, but rather estimated whether in idual responses to training can be detected with the current exercise protocol. After a repeated intervention, in idual responses to 4 weeks of HIIT were not consistent, whereas repeated testing during the 12-week-long intervention was able to capture in idual responses to HIIT. The reliability trial should not be used to study in idual responses, rather should be used to classify participants as responders with a certain level of confidence. 12 weeks of HIIT with repeated testing during the intervention is sufficient and cost-effective to measure in idual responses to exercise training since it allows for a confident estimate of an in idual's true response. Our study has significant implications for how to improve the design of exercise studies to accurately estimate in idual responses to exercise training interventions. HighlightsWhat are the findings?We implemented five statistical methods in a single study to estimate the magnitude of within-subject variability and quantify responses to exercise training at the in idual level.The various proposed methods used to estimate in idual responses to training provide different types of information and rely on different assumptions that are difficult to test.Within-subject variability is often large in magnitude, and as such, should be systematically evaluated and carefully considered in future studies to successfully estimate in idual responses to training.
Publisher: F1000 Research Ltd
Date: 31-08-2018
DOI: 10.12688/F1000RESEARCH.15258.1
Abstract: The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.
Publisher: American Physiological Society
Date: 09-2018
DOI: 10.1152/JAPPLPHYSIOL.00344.2018
Abstract: Angiotensin-converting enzyme (ACE) is expressed in human skeletal muscle. The ACE I/D polymorphism has been associated with athletic performance in some studies. Studies have suggested that the ACE I/D gene variant is associated with ACE enzyme content in serum, and there is an interaction between ACE and uncoupling proteins 2 and 3 (UCP2 and UCP3). However, no studies have explored the effect of ACE I/D on ACE, UCP2, and UCP3 protein content in human skeletal muscle. Utilizing the Gene SMART cohort ( n = 81), we investigated whether the ACE I/D gene variant is associated with ACE enzyme content in blood and ACE, UCP2, and UCP3 protein content in skeletal muscle at baseline and following a session of high-intensity interval exercise (HIIE). Using a stringent and robust statistical analyses, we found that the ACE I/D gene variant was associated with ACE enzyme content in blood ( P 0.005) at baseline but not the ACE, UCP2, and UCP3 protein content in muscle at baseline. A single session of HIIE tended (0.005 P 0.05) to increase blood ACE content immediately postexercise, whereas muscle ACE protein content was lower 3 h after a single session of HIIE ( P 0.005). Muscle UCP3 protein content decreased immediately after a single session of HIIE ( P 0.005) and remained low 3 h postexercise. However, those changes in the muscle were not genotype dependent. In conclusion, The ACE I/D gene variant predicts ACE enzyme content in blood but not the ACE, UCP2, and UCP3 protein content of human skeletal muscle. NEW & NOTEWORTHY This paper describes the association between ACE I/D gene variant and ACE protein content in blood and ACE, UCP2, and UCP3 protein content in skeletal muscle at baseline and after exercise in a large cohort of healthy males. Our data suggest that ACE I/D is a strong predictor of blood ACE content but not muscle ACE content.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2016
Publisher: Springer Science and Business Media LLC
Date: 02-05-2022
DOI: 10.1038/S41576-022-00477-6
Abstract: Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of in idual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2020
DOI: 10.1007/S00438-019-01639-8
Abstract: Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study n = 58 and Hawaiian Ironman Triathlon 2008 n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO
Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41598-020-72730-Z
Abstract: Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for pathways-in-cancer (including focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15 , DYRK2 , FHL2 , MRPS33 , ABCA17P . Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6–8 CpGs in the HOX family of genes altered with age. With HOXD10 , HOXD9 , HOXD8 , HOXA3 , HOXC9 , HOXB1 , HOXB3 , HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3 ) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8 , HOXC9 , HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1 , HOXA3 and HOXC-AS3 . Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.
Publisher: Cold Spring Harbor Laboratory
Date: 28-09-2020
DOI: 10.1101/2020.09.28.315838
Abstract: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by aging in humans. Using a large-scale epigenome-wide association study (EWAS) meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 human muscle methylomes), we identified 9,986 differentially methylated regions at a stringent false discovery rate 0.005, spanning 8,748 unique genes, many of which related to skeletal muscle structure and development. We then integrated the DNA methylation results with known transcriptomic and proteomic age-related changes in skeletal muscle, and found that even though most differentially methylated genes are not altered at the mRNA or protein level, they are nonetheless strongly enriched for genes showing age-related differential expression. We provide here the most comprehensive picture of DNA methylation aging in human skeletal muscle, and have made our results available as an open-access, user-friendly, web-based tool called MetaMeth ( sarah-voisin.shinyapps.io/MetaMeth/ ).
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2021
DOI: 10.1101/2021.03.16.435733
Abstract: Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation, however this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle s les (222 males, 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci, however these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen ( AR ), estrogen ( ESR1 ), and glucocorticoid ( NR3C1 ) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16 % of sex-biased DNA methylation loci (FDR 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p-value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes ( FOXO3A, ALDH1A1 , and GGT7 ) in the Gene SMART cohort with qPCR. GGT7 , involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8,420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health. The importance of uncovering biological sex differences and their translation to physiology has become increasingly evident. Using a large-scale meta-analysis of three cohorts, we perform the first comparison of genome-wide skeletal muscle DNA methylation between males and females, and identify thousands of genes that display sex-differential methylation. We then explore intrinsic biological factors that may be underlying the DNA methylation sex differences, such as fibre type proportions and sex hormones. Leveraging the GTEx database, we identify hundreds of genes with both sex-differential expression and DNA methylation in skeletal muscle. We further confirm the sex-biased genes with gene expression data from two cohorts included in the methylation meta-analysis. Our study integrates genomewide sex-biased DNA methylation and expression in skeletal muscle, shedding light on distinct sex differences in skeletal muscle.
Publisher: Informa UK Limited
Date: 13-05-2019
Publisher: Wiley
Date: 07-12-2021
DOI: 10.1113/JP279499
Abstract: Sex differences in exercise physiology, such as substrate metabolism and skeletal muscle fatigability, stem from inherent biological factors, including endogenous hormones and genetics. Studies investigating exercise physiology frequently include only males or do not take sex differences into consideration. Although there is still an underrepresentation of female participants in exercise research, existing studies have identified sex differences in physiological and molecular responses to exercise training. The observed sex differences in exercise physiology are underpinned by the sex chromosome complement, sex hormones and, on a molecular level, the epigenome and transcriptome. Future research in the field should aim to include both sexes, control for menstrual cycle factors, conduct large‐scale and ethnically erse studies, conduct meta‐analyses to consolidate findings from various studies, leverage unique cohorts (such as post‐menopausal, transgender, and those with sex chromosome abnormalities), as well as integrate tissue and cell‐specific ‐omics data. This knowledge is essential for developing deeper insight into sex‐specific physiological responses to exercise training, thus directing future exercise physiology studies and practical application. image
Publisher: Public Library of Science (PLoS)
Date: 09-06-2016
Publisher: Cold Spring Harbor Laboratory
Date: 20-02-2020
DOI: 10.1101/2020.02.20.957340
Abstract: Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n=62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but nine nuclear encoded variants in eight separate genes were found to be associated with exercise responses (FDR .05) (rs11061368: DIABLO, rs113400963: FAM185A, rs6062129 and rs6121949: MTG2, rs7231304: AFG3L2, rs2041840: NDUFAF7, rs7085433: TIMM23, rs1063271: SPTLC2, rs2275273: ALDH18A1). Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities. Previous exercise genetic studies contain many flaws that impede the growth in knowledge surrounding change in exercise outcomes. In particular, exercise studies looking at mtDNA variants have looked at very small portions of the mitochondrial genome. Mitochondria are the ‘power house’ of the cell and therefore understanding the mitochondrial genetics behind adaptations to training can help us fill knowledge gaps in current research. Here, we utilised a new mitochondrial genetic sequencing technique to examine all mitochondrial and mitochondrial related genetic variations. We have shown that there were no mitochondrial specific variants that influenced exercise training however there were 9 related variants that were significantly associated with exercise phenotypes. Additionally, we have shown that building composite traits increased the significance of our association testing and lead to novel findings. We will be able to understand why response to training is so varied and increase the effectiveness of exercise training on a host of metabolic disorders.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2020
DOI: 10.1038/S41598-020-67870-1
Abstract: Mitochondria supply intracellular energy requirements during exercise. Specific mitochondrial haplogroups and mitochondrial genetic variants have been associated with athletic performance, and exercise responses. However, these associations were discovered using underpowered, candidate gene approaches, and consequently have not been replicated. Here, we used whole-mitochondrial genome sequencing, in conjunction with high-throughput genotyping arrays, to discover novel genetic variants associated with exercise responses in the Gene SMART (Skeletal Muscle Adaptive Response to Training) cohort (n = 62 completed). We performed a Principal Component Analysis of cohort aerobic fitness measures to build composite traits and test for variants associated with exercise outcomes. None of the mitochondrial genetic variants but eight nuclear encoded variants in seven separate genes were found to be associated with exercise responses (FDR 0.05) ( rs11061368 : DIABLO , rs113400963 : FAM185A , rs6062129 and rs6121949 : MTG2 , rs7231304 : AFG3L2 , rs2041840 : NDUFAF7 , rs7085433 : TIMM23 , rs1063271 : SPTLC2 ) . Additionally, we outline potential mechanisms by which these variants may be contributing to exercise phenotypes. Our data suggest novel nuclear-encoded SNPs and mitochondrial pathways associated with exercise response phenotypes. Future studies should focus on validating these variants across different cohorts and ethnicities.
Publisher: Georg Thieme Verlag KG
Date: 21-07-2021
DOI: 10.1055/A-1198-5496
Abstract: This review summarised robust and consistent genetic variants associated with aerobic-related and resistance-related phenotypes. In total we highlight 12 SNPs and 7 SNPs that are robustly associated with variance in aerobic-related and resistance-related phenotypes respectively. To date, there is very little literature ascribed to understanding the interplay between genes and environmental factors and the development of physiological traits. We discuss future directions, including large-scale exercise studies to elucidate the functional relevance of the discovered genomic markers. This approach will allow more rigour and reproducible research in the field of exercise genomics.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.BONE.2019.03.015
Abstract: Osteocalcin (OC) is used as a surrogate marker for bone turnover in clinical settings. As bone mineral density (BMD) is largely heritable, we tested the hypothesis that a) bone-associated genetic variants previously identified in Genome-Wide Association Studies (GWAS) and combined into a genetic risk score (GRS) are associated with a) circulating levels of OC and b) the changes in OC following acute exercise. Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 73 healthy Caucasian males at baseline and after a single bout of high-intensity interval exercise. In addition, genotyping was conducted targeting GWAS variants previously reported to be associated with BMD and then combined into a GRS. Potential associations between the GRS and tOC, ucOC and cOC were tested with linear regressions adjusted for age. At baseline none of the in idual SNPs associated with tOC, ucOC and cOC. However, when combined, a higher GRS was associated with higher tOC (β = 0.193 ng/mL p = 0.037 95% CI = 0.012, 0.361) and cOC (β = 0.188 ng/mL p = 0.04 95% CI = 0.004, 0.433). Following exercise, GRS was associated with ucOC levels, (β = 3.864 ng/mL p-value = 0.008 95% CI = 1.063, 6.664) but not with tOC or cOC. Screening for genetic variations may assist in identifying people at risk for abnormal circulating levels of OC at baseline/rest. Genetic variations in BMD predicted the ucOC response to acute exercise indicating that physiological functional response to exercise may be influenced by bone-related gene variants.
Publisher: Wiley
Date: 09-01-2020
Publisher: Wiley
Date: 17-02-2020
DOI: 10.1002/JCSM.12556
Publisher: Springer Science and Business Media LLC
Date: 03-01-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
DOI: 10.1249/JES.0000000000000176
Abstract: The in idual response to exercise training is of great interest with methods that have been proposed to measure this response reviewed in this paper. However, in idual training response estimates may be biased by various sources of variability present in exercise studies, and in particular by within-subject variability. We propose the use of protocols that can separate trainability from within-subject variability.
Publisher: Bioscientifica
Date: 08-2018
DOI: 10.1530/REP-17-0689
Abstract: The POU5F1 gene encodes one of the ‘core’ transcription factors necessary to establish and maintain pluripotency in mammals. Its function depends on its precise level of expression, so its transcription has to be tightly regulated. To date, few conserved functional elements have been identified in its 5′ regulatory region: a distal and a proximal enhancer, and a minimal promoter, epigenetic modifications of which interfere with POU5F1 expression and function in in vitro -derived cell lines. Also, its permanent inactivation in differentiated cells depends on de novo methylation of its promoter. However, little is known about the epigenetic regulation of POU5F1 expression in the embryo itself. We used the rabbit blastocyst as a model to analyze the methylation dynamics of the POU5F1 5′ upstream region, relative to its regulated expression in different compartments of the blastocyst over a 2-day period of development. We evidenced progressive methylation of the 5′ regulatory region and the first exon accompanying differentiation and the gradual repression of POU5F1 . Methylation started in the early trophectoderm before complete transcriptional inactivation. Interestingly, the distal enhancer, which is known to be active in naïve pluripotent cells only, retained a very low level of methylation in primed pluripotent epiblasts and remained less methylated in differentiated compartments than the proximal enhancer. This detailed study identified CpGs with the greatest variations in methylation, as well as groups of CpGs showing a highly correlated behavior, during differentiation. Moreover, our findings evidenced few CpGs with very specific behavior during this period of development.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2015
Publisher: Wiley
Date: 19-11-2015
DOI: 10.1111/APHA.12414
Abstract: The response to exercise training (trainability) has been shown to have a strong heritable component. There is growing evidence suggesting that traits such as trainability do not only depend on the genetic code, but also on epigenetic signals. Epigenetic signals play an important role in the modulation of gene expression, through mechanisms such as DNA methylation and histone modifications. There is an emerging evidence to show that physical activity influences DNA methylation in humans. The present review aims to summarize current knowledge on the link between DNA methylation and physical activity in humans. We have critically reviewed the literature and only papers focused on physical activity and its influence on DNA methylation status were included a total of 25 papers were selected. We concluded that both acute and chronic exercises significantly impact DNA methylation, in a highly tissue- and gene-specific manner. This review also provides insights into the molecular mechanisms of exercise-induced DNA methylation changes, and recommendations for future research.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.BONE.2019.115085
Abstract: Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The carboxylated (cOC) and undercarboxylated (ucOC) forms may have a different biological function but age-specific reference ranges for these components are not established. Given the different physiological roles, development of reference ranges may help to identify people at risk for bone disease. Blood was collected in the morning after an overnight fast from 236 adult men (18 to 92 years old) free of diabetes, antiresorptive, warfarin or glucocorticoid use. Serum was analyzed for total osteocalcin (tOC) and the ucOC fraction using the hydroxyapatite binding method. cOC, ucOC/tOC and cOC/tOC ratios were calculated. Reference intervals were established by polynomial quantile regression analysis. The normal ranges for young men (≤30 years) were: tOC 17.9-56.8 ng/mL, ucOC 7.1-22.0 ng/mL, cOC 8.51-40.3 ng/mL (2.5th to 97.5th quantiles). Aging was associated with a "U" shaped pattern for tOC, cOC and ucOC levels. ucOC/tOC ratio was higher, while cOC/tOC ratio was lower in men of advanced age. Age explained ∼31%, while body mass index explained ∼4%, of the variance in the ratios. We have defined normal reference ranges for the OC forms in Australian men and demonstrated that the OC ratios may be better measures, than the absolute values, to identify the age-related changes on OC in men. These ratios may be incorporated into future research and clinical trials, and their associations with prediction of events, such as fracture or diabetes risk, should be determined.
Publisher: EDP Sciences
Date: 2015
DOI: 10.1051/JBIO/2015021
Publisher: Informa UK Limited
Date: 13-04-2019
Publisher: Informa UK Limited
Date: 19-12-2019
Start Date: 2019
End Date: 2021
Funder: Jack Brockhoff Foundation
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: Defence Science and Technology Group
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 12-2024
Amount: $444,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2019
End Date: 12-2022
Amount: $302,500.00
Funder: Australian Research Council
View Funded Activity