The methylome and comparative transcriptome after high intensity sprint exercise in human skeletal muscle

Abstract

The methylome and transcriptome signature following exercise that is physiologically and metabolic relevant to sporting contexts such as team sports or health prescription scenarios (e.g. high intensity interval training/HIIT) has not been investigated. To explore this, we undertook two different sport/exercise relevant high-intensity sprint running protocols in humans using a repeated measures design of: 1) Change of direction (COD) versus; 2) straight line (ST) sprint exercise. We took skeletal muscle biopsies from the vastus lateralis 30 minutes and 24 hours post exercise followed by 850K methylation arrays and comparative analysis with recent sprint and acute aerobic exercise meta-analysis transcriptomes. Despite matched intensity (speed x distance and number of accelerations/decelerations) between COD and ST exercise, COD exercise elicited greater movement (GPS Playerload™), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) loading compared with ST exercise. The exercise response alone across both conditions evoked extensive alterations in the methylome immediately post and 24 hrs after exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST sprint exercise, particularly enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. A finding that was more prominent immediately post exercise. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of the genes altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we discovered that VEGFA and its downstream nuclear transcription factor, NR4A1 had enriched hypomethylation within their promoter regions. VEGFA and NR4A1 were also significantly upregulated in the sprint transcriptome and meta-analysis of exercise transcriptomes. We confirmed increased mRNA expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes, PGC1-α and NR4A3, 3 hrs post COD vs. ST exercise. Overall, we demonstrate that increased physiological load via change of direction sprint exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise. These data imply that introducing changes in direction into high intensity running protocols could serve as an important modulator of a favourable epigenomic and transcriptomic landscape in response to exercise in athletes and trigger greater skeletal muscle remodelling through enhanced gene expression.

Genetic and Epigenetic Regulation of Skeletal Muscle Ribosome Biogenesis with Exercise

“…In muscle undergoing hypertrophy, histone modifications at the rDNA promoter coincide with increased rDNA transcription (von Walden et al, 2012). In light of this epigenetic regulation of rDNA during muscle cell growth, and in context with prior studies reporting genome-wide promoter methylation changes with acute exercise (Barres et al, 2012;Sharples et al, 2016;Seaborne et al, 2018;Turner et al, 2019;Maasar et al 2020), we hypothesized that CpG methylation changes to the rDNA promoter region may associate with the response to RE in muscle; however, this was not the case. rDNA promoter methylation in our adult muscle samples was low at rest (~20% on average), consistent with our previous report in children (von Walden et al, 2020b), suggesting the promoter is generally available for transcription in a CpG methylation context, and this does not change with acute EE or RE.…”

The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle

“…The patients/participants provided their written informed consent to participate in this study. This manuscript has been released as a pre-print at BioRxiv (Maasar et al, 2020).…”

Human skeletal muscle methylome after low carbohydrate energy balanced exercise

“…It is currently unknown what the impact of achieving energy balance under low-CHO conditions has on the SkM response to exercise using an untargeted whole-genome ´omic´ approach. The epigenetic modification of DNA methylation across the genome (methylome) has been demonstrated to be a dynamic response that precedes changes in gene expression in SkM after acute exercise (14)(15)(16). Both acute exercise and chronic training can predominantly decrease DNA methylation (i.e., hypomethylation) in both human and rodent SkM (14)(15)(16)(17)(18)(19)(20).…”

“…The epigenetic modification of DNA methylation across the genome (methylome) has been demonstrated to be a dynamic response that precedes changes in gene expression in SkM after acute exercise (14)(15)(16). Both acute exercise and chronic training can predominantly decrease DNA methylation (i.e., hypomethylation) in both human and rodent SkM (14)(15)(16)(17)(18)(19)(20). This is perhaps because hypomethylation, especially in gene regulatory regions such as promoters, allows transcription factor binding to enable gene expression to occur (21,22).…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted January 20, 2023. ; https://doi.org/10.1101/2023.01. 19.524676 doi: bioRxiv preprint (16,19), high-intensity (15) and aerobic exercise (18,23,24). Importantly, DNA methylome studies have identified novel exercise-responsive genes in human SkM that have not been previously highlighted in mRNA/transcriptome studies (14,25,26).…”