Many transgender (trans) individuals utilize gender-affirming hormone therapy (GAHT) to promote changes in secondary sex characteristics to affirm their gender. Participation rates of trans people in sport are exceedingly low, yet given high rates of depression and increased cardiovascular risk, the potential benefits of sports participation are great. In this review, we provide an overview of the evidence surrounding the effects of GAHT on multiple performance-related phenotypes, as well as current limitations. Whilst data is clear that there are differences between males and females, there is a lack of quality evidence assessing the impact of GAHT on athletic performance. Twelve months of GAHT leads to testosterone concentrations that align with reference ranges of the affirmed gender. Feminizing GAHT in trans women increases fat mass and decreases lean mass, with opposite effects observed in trans men with masculinizing GAHT. In trans men, an increase in muscle strength and athletic performance is observed. In trans women, muscle strength is shown to decrease or not change following 12 months of GAHT. Haemoglobin, a measure of oxygen transport, changes to that of the affirmed gender within 6 months of GAHT, with very limited data to suggest possible reductions in maximal oxygen uptake as a result of feminizing GAHT. Current limitations of this field include a lack of long-term studies, adequate group comparisons and adjustment for confounding factors (e.g. height and lean body mass), and small sample sizes. There also remains limited data on endurance, cardiac or respiratory function, with further longitudinal studies on GAHT needed to address current limitations and provide more robust data to inform inclusive and fair sporting programmes, policies and guidelines.
Nearly all human complex traits and diseases exhibit some degree of sex differences, and epigenetics contributes to these differences as DNA methylation shows sex differences in various tissues. However, skeletal muscle epigenetic sex differences remain largely unexplored, yet skeletal muscle displays distinct sex differences at the transcriptome level. We conducted a large-scale meta-analysis of autosomal DNA methylation sex differences in human skeletal muscle in three separate cohorts (Gene SMART, FUSION, and GSE38291), totalling n = 369 human muscle samples (n = 222 males, n = 147 females). 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 metabolism. We then integrated our epigenetic results with transcriptomic data from the GTEx database and the FUSION cohort. Altogether, we identified 326 autosomal genes that display sex differences at both the DNA methylation, and transcriptome levels. Importantly, sex-biased genes at the transcriptional level were overrepresented among the sex-biased genes at the epigenetic level (p-value = 4.6e-13), which suggests differential DNA methylation and gene expression between males and females in 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 muscle metabolism, displays male-biased expression in skeletal muscle across the three cohorts, as well as lower methylation in males. In conclusion, we uncovered thousands of genes that exhibit DNA methylation differences between the males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.
Lipocalin-2 (LCN2), a hormone produced by adipocytes, osteoblasts, and renal tubular cells, is implicated in age-related diseases, including cardio-metabolic disease. To understand the role LCN2 may play in pathological states, we first need to elucidate the relationship between circulating LCN2 with indices of cardio-metabolic health during "normal" aging. This study examined the relationship between serum levels of LCN2, age, and cardio-metabolic measures across the adult lifespan in males and females. We conducted a pooled cohort analysis including 124 community-dwelling males (n = 52) and females (n = 72) (age 20-87 yr, median BMI 25.92 [23.04, 29.81] kg/m2). Serum LCN2 was analyzed using a two-step chemiluminescent microparticle monoclonal immunoassay. The relationship between LCN2 and age was evaluated by linear regression and cubic spline. Simple linear regressions were performed to investigate the relationship between LCN2 and the following variables: BMI, VO2peak, serum glucose, and body composition (DXA). For every 1 yr increase in age, LCN2 levels were 0.26 mg/L higher (P = .007, 95% CI [0.07, 0.45]). Each 1 unit increase in BMI (kg/m2) was associated with 0.88 mg/L higher LCN2 levels (P = .027, [0.10, 1.66]) and each 1 unit increase in VO2peak (mL/kg/min) was associated with 0.38 mg/L lower LCN2 (p = .003, [-0.63, -0.13]).There was no significant relationship between LCN2 and sex, glucose levels or body composition (all p > .05). LCN2 increased linearly across the adult lifespan while it decreased as fitness level increased. Future research should build on these findings to determine whether LCN2 can be used as a biomarker for chronic disease and if exercise can mitigate age-related disease associated with LCN2 changes.
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 ( https://sarah-voisin.shinyapps.io/MetaMeth/ ).
Additional file 9. KEGG (DMRs). Kyoto Encyclopedia of Genes and Genomes pathways identified with GSEA using the differentially methylated regions. Description of KEGG pathway, N represents the total number of genes in the KEGG pathway, DE represents the number of differentially methylated genes in the KEGG pathway, and SigGenesInSet are the differentially methylated genes in the KEGG pathway.
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 samples (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. Significance 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.
Additional file 5. Overlapping genes. Genes which displayed sex-biased gene expression in GTEx and FUSION as well as sex-biased DNA methylation (according to DMRs) in the meta-analysis. Corresponding chromosome, ensemble gene ID, gene name, GTEx mash posterior effect size, GTEx local false sign rate threshold, FUSION mRNA fold change, FUSION mRNA FDR, and number of DMPs per gene. Positive effect sizes indicate higher DNA methylation or expression in males compared to females.
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