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

ABSTRACT: The methylome and transcriptome signatures following exercise that are physiologically and metabolically 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 performed two different sport/exercise relevant high-intensity running protocols in five male sport team members using a repeated measures design of: (1) change of direction (COD) versus; (2) straight line (ST) running exercise with a wash-out period of at least 2 weeks between trials. Skeletal muscle biopsies collected from the vastus lateralis 30 min and 24 h post exercise, were assayed using 850K methylation arrays and a comparative analysis with recent (subject-unmatched) sprint and acute aerobic exercise meta-analysis transcriptomes was performed. Despite COD and ST exercise being matched for classically defined intensity measures (speed × distance and number of accelerations/decelerations), COD exercise elicited greater movement (GPS-Playerload), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) exertion measures compared with ST exercise, suggesting COD exercise evoked a higher exercise intensity. The exercise response alone across both conditions evoked extensive alterations in the methylome 30 min and 24 h post exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST exercise, particularly at 30 min post exercise, enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of genes that were altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we observed 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 also confirmed increased gene expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes PPARGC1A (that encodes PGC1-?) and NR4A3 in COD vs. ST exercise. Overall, we demonstrate that increased physiological/metabolic load via COD exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise.

SUBMITTER: Maasar MF

PROVIDER: S-EPMC7933519 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Maasar Mohd-Firdaus MF Turner Daniel C DC Gorski Piotr P PP Seaborne Robert A RA Strauss Juliette A JA Shepherd Sam O SO Cocks Matt M Pillon Nicolas J NJ Zierath Juleen R JR Hulton Andrew T AT Drust Barry B Sharples Adam P AP

Frontiers in physiology 20210219

The methylome and transcriptome signatures following exercise that are physiologically and metabolically 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 performed two different sport/exercise relevant high-intensity running protocols in five male sport team members using a repeated measures design of: (1) change of direction (COD) versus; (2) straight line (ST) running ...[more]

PMID: 33679435

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Project description:The methylome and transcriptome signatures following exercise that are physiologically and metabolically 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 performed two different sport/exercise relevant high-intensity running protocols in 5 male sport team members using a repeated measures design of: 1) Change of direction (COD) versus; 2) straight line (ST) exercise with a wash-out period of at least 2 weeks between trials. Skeletal muscle biopsies collected from the vastus lateralis 30 minutes and 24 hours post exercise, were assayed using 850K methylation arrays and a comparative analysis with recent (subject-unmatched) sprint and acute aerobic exercise meta-analysis transcriptomes was performed. Despite COD and ST exercise being matched for classically defined intensity measures (speed x distance and number of accelerations/decelerations), COD exercise elicited greater movement (GPS-Playerload), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) measures compared with ST exercise, suggesting COD exercise evoked a higher exercise intensity. The exercise response alone across both conditions evoked extensive alterations in the methylome 30 mins and 24 hrs post exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST exercise, particularly at 30 minutes post exercise, enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of genes that were altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we observed 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 gene expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes, PPARGC1A (that encodes PGC1-α) and NR4A3 in COD vs. ST exercise. Overall, we demonstrate that increased physiological/metabolic load via change of direction exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise.

Project description:Long-distance running competitions impose a large amount of mechanical loading and strain leading to muscle edema and delayed onset muscle soreness (DOMS). Damage to various muscle fibers, metabolic impairments and fatigue have been linked to explain how DOMS impairs muscle function. Disruptions of muscle fiber during DOMS exacerbated by exercise have been shown to change muscle mechanical properties. The objective of this study is to quantify changes in mechanical properties of different muscles in the thigh and lower leg as function of running distance and time after competition. A custom implementation of Focused Comb-Push Ultrasound Shear Elastography (F-CUSE) method was used to evaluate shear modulus in runners before and after a race. Twenty-two healthy individuals (age: 23 ± 5 years) were recruited using convenience sampling and split into three race categories: short distance (nine subjects, 3-5 miles), middle distance (10 subjects, 10-13 miles), and long distance (three subjects, 26+ miles). Shear Wave Elastography (SWE) measurements were taken on both legs of each subject on the rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM), soleus, lateral gastrocnemius (LG), medial gastrocnemius (MG), biceps femoris (BF) and semitendinosus (ST) muscles. For statistical analyses, a linear mixed model was used, with recovery time and running distance as fixed variables, while shear modulus was used as the dependent variable. Recovery time had a significant effect on the soleus (p = 0.05), while running distance had considerable effect on the biceps femoris (p = 0.02), vastus lateralis (p < 0.01) and semitendinosus muscles (p = 0.02). Sixty-seven percent of muscles exhibited a decreasing stiffness trend from before competition to immediately after competition. The preliminary results suggest that SWE could potentially be used to quantify changes of muscle mechanical properties as a way for measuring recovery procedures for runners.

Project description:Transcriptome wide changes in human skeletal muscle after acute (anabolic) and chronic resistance exercise (RE) induced hypertrophy have been extensively determined in the literature. We have also recently undertaken DNA methylome analysis (850,000?+?CpG sites) in human skeletal muscle after acute and chronic RE, detraining and retraining, where we identified an association between DNA methylation and epigenetic memory of exercise induced skeletal muscle hypertrophy. However, it is currently unknown as to whether all the genes identified in the transcriptome studies to date are also epigenetically regulated at the DNA level after acute, chronic or repeated RE exposure. We therefore aimed to undertake large scale bioinformatical analysis by pooling the publicly available transcriptome data after acute (110 samples) and chronic RE (181 samples) and comparing these large data sets with our genome-wide DNA methylation analysis in human skeletal muscle after acute and chronic RE, detraining and retraining. Indeed, after acute RE we identified 866 up- and 936 down-regulated genes at the expression level, with 270 (out of the 866 up-regulated) identified as being hypomethylated, and 216 (out of 936 downregulated) as hypermethylated. After chronic RE we identified 2,018 up- and 430 down-regulated genes with 592 (out of 2,018 upregulated) identified as being hypomethylated and 98 (out of 430 genes downregulated) as hypermethylated. After KEGG pathway analysis, genes associated with 'cancer' pathways were significantly enriched in both bioinformatic analysis of the pooled transcriptome and methylome datasets after both acute and chronic RE. This resulted in 23 (out of 69) and 28 (out of 49) upregulated and hypomethylated and 12 (out of 37) and 2 (out of 4) downregulated and hypermethylated 'cancer' genes following acute and chronic RE respectively. Within skeletal muscle tissue, these 'cancer' genes predominant functions were associated with matrix/actin structure and remodelling, mechano-transduction (e.g. PTK2/Focal Adhesion Kinase and Phospholipase D- following chronic RE), TGF-beta signalling and protein synthesis (e.g. GSK3B after acute RE). Interestingly, 51 genes were also identified to be up/downregulated in both the acute and chronic RE pooled transcriptome analysis as well as significantly hypo/hypermethylated after acute RE, chronic RE, detraining and retraining. Five genes; FLNB, MYH9, SRGAP1, SRGN, ZMIZ1 demonstrated increased gene expression in the acute and chronic RE transcriptome and also demonstrated hypomethylation in these conditions. Importantly, these 5 genes demonstrated retained hypomethylation even during detraining (following training induced hypertrophy) when exercise was ceased and lean mass returned to baseline (pre-training) levels, identifying them as genes associated with epigenetic memory in skeletal muscle. Importantly, for the first time across the transcriptome and epigenome combined, this study identifies novel differentially methylated genes associated with human skeletal muscle anabolism, hypertrophy and epigenetic memory.

Dataset Information

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

Publications

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

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