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

Mohd Firdaus Maasar; Daniel C. Turner; Piotr P. Gorski; Robert A. Seaborne; Juliette A. Strauss; Sam O. Shepherd; Matt Cocks; Nicolas J. Pillon; Juleen R. Zierath; Andrew T. Hulton; Barry Drust; Adam P. Sharples

doi:10.3389/fphys.2021.619447

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

Mohd Firdaus Maasar, Daniel C. Turner, Piotr P. Gorski, Robert A. Seaborne, Juliette A. Strauss, Sam O. Shepherd, Matt Cocks, Nicolas J. Pillon, Juleen R. Zierath, Andrew T. Hulton, Barry Drust^*, Adam P. Sharples^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Downloads (Pure)

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-α) 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.

Original language	English
Article number	619447
Number of pages	17
Journal	Frontiers in Physiology
Volume	12
DOIs	https://doi.org/10.3389/fphys.2021.619447
Publication status	Published - 19 Feb 2021

Bibliographical note

Funding Information:
We would like to thank the Malaysian government agency: Majlis Amanah Rakyat (MARA) for funding this research. Funding. M-FM received a funded Ph.D. scholarship via the Malaysian government agency: Majlis Amanah Rakyat (MARA) via BD, AS, and AH. This work was supported by the United Kingdom’s Engineering and Physical Sciences Research Council (EPSRC) and the United Kingdom Medical Research Council’s (MRC) center for doctoral training, via a studentship awarded to PG in the group of AS (PI). These data were also supported by a North Staffordshire Medical Institute (NMSI), the Society for Endocrinology and Glaxosmithkline grants awarded to AS (PI). Funds from Liverpool John Moores University (United Kingdom) The Norwegian School of Sport Sciences, Oslo (Norway) and The University of Birmingham (United Kingdom) supported the Ph.D. work by M-FM, DT, PG, and RS in the groups of AS and BD. JZ was supported from the Swedish Research Council for Sport Science (P2018-0097) and the Swedish Research Council (Vetenskapsrådet) (2015-00165). NP was supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission, 704978). This manuscript has been released as a pre-print at BioRxiv (Maasar et al., 2020).

Publisher Copyright:
© Copyright © 2021 Maasar, Turner, Gorski, Seaborne, Strauss, Shepherd, Cocks, Pillon, Zierath, Hulton, Drust and Sharples.

Keywords

AMPK
change of direction
DNA methylation
MAPK
NR4A1 (Nur77)
NR4A3
PGC1 alpha
VEGF

ASJC Scopus subject areas

Physiology
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3389/fphys.2021.619447Licence: Creative Commons: Attribution (CC BY)

MaasarM2021ComparativeFinal published version, 3.7 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

Maasar, M. F., Turner, D. C., Gorski, P. P., Seaborne, R. A., Strauss, J. A., Shepherd, S. O., Cocks, M., Pillon, N. J., Zierath, J. R., Hulton, A. T., Drust, B., & Sharples, A. P. (2021). The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle. Frontiers in Physiology, 12, Article 619447. https://doi.org/10.3389/fphys.2021.619447

@article{61620d0b32b1471196c24eec7c471fab,

title = "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-α) 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.",

keywords = "AMPK, change of direction, DNA methylation, MAPK, NR4A1 (Nur77), NR4A3, PGC1 alpha, VEGF",

author = "Maasar, {Mohd Firdaus} and Turner, {Daniel C.} and Gorski, {Piotr P.} and Seaborne, {Robert A.} and Strauss, {Juliette A.} and Shepherd, {Sam O.} and Matt Cocks and Pillon, {Nicolas J.} and Zierath, {Juleen R.} and Hulton, {Andrew T.} and Barry Drust and Sharples, {Adam P.}",

note = "Funding Information: We would like to thank the Malaysian government agency: Majlis Amanah Rakyat (MARA) for funding this research. Funding. M-FM received a funded Ph.D. scholarship via the Malaysian government agency: Majlis Amanah Rakyat (MARA) via BD, AS, and AH. This work was supported by the United Kingdom{\textquoteright}s Engineering and Physical Sciences Research Council (EPSRC) and the United Kingdom Medical Research Council{\textquoteright}s (MRC) center for doctoral training, via a studentship awarded to PG in the group of AS (PI). These data were also supported by a North Staffordshire Medical Institute (NMSI), the Society for Endocrinology and Glaxosmithkline grants awarded to AS (PI). Funds from Liverpool John Moores University (United Kingdom) The Norwegian School of Sport Sciences, Oslo (Norway) and The University of Birmingham (United Kingdom) supported the Ph.D. work by M-FM, DT, PG, and RS in the groups of AS and BD. JZ was supported from the Swedish Research Council for Sport Science (P2018-0097) and the Swedish Research Council (Vetenskapsr{\aa}det) (2015-00165). NP was supported by an Individual Fellowship from the Marie Sk{\l}odowska-Curie Actions (European Commission, 704978). This manuscript has been released as a pre-print at BioRxiv (Maasar et al., 2020). Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Maasar, Turner, Gorski, Seaborne, Strauss, Shepherd, Cocks, Pillon, Zierath, Hulton, Drust and Sharples.",

year = "2021",

month = feb,

day = "19",

doi = "10.3389/fphys.2021.619447",

language = "English",

volume = "12",

journal = "Frontiers in Physiology",

issn = "1664-042X",

publisher = "Frontiers",

}

Maasar, MF, Turner, DC, Gorski, PP, Seaborne, RA, Strauss, JA, Shepherd, SO, Cocks, M, Pillon, NJ, Zierath, JR, Hulton, AT, Drust, B & Sharples, AP 2021, 'The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle', Frontiers in Physiology, vol. 12, 619447. https://doi.org/10.3389/fphys.2021.619447

TY - JOUR

T1 - The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle

AU - Maasar, Mohd Firdaus

AU - Turner, Daniel C.

AU - Gorski, Piotr P.

AU - Seaborne, Robert A.

AU - Strauss, Juliette A.

AU - Shepherd, Sam O.

AU - Cocks, Matt

AU - Pillon, Nicolas J.

AU - Zierath, Juleen R.

AU - Hulton, Andrew T.

AU - Drust, Barry

AU - Sharples, Adam P.

N1 - Funding Information: We would like to thank the Malaysian government agency: Majlis Amanah Rakyat (MARA) for funding this research. Funding. M-FM received a funded Ph.D. scholarship via the Malaysian government agency: Majlis Amanah Rakyat (MARA) via BD, AS, and AH. This work was supported by the United Kingdom’s Engineering and Physical Sciences Research Council (EPSRC) and the United Kingdom Medical Research Council’s (MRC) center for doctoral training, via a studentship awarded to PG in the group of AS (PI). These data were also supported by a North Staffordshire Medical Institute (NMSI), the Society for Endocrinology and Glaxosmithkline grants awarded to AS (PI). Funds from Liverpool John Moores University (United Kingdom) The Norwegian School of Sport Sciences, Oslo (Norway) and The University of Birmingham (United Kingdom) supported the Ph.D. work by M-FM, DT, PG, and RS in the groups of AS and BD. JZ was supported from the Swedish Research Council for Sport Science (P2018-0097) and the Swedish Research Council (Vetenskapsrådet) (2015-00165). NP was supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission, 704978). This manuscript has been released as a pre-print at BioRxiv (Maasar et al., 2020). Publisher Copyright: © Copyright © 2021 Maasar, Turner, Gorski, Seaborne, Strauss, Shepherd, Cocks, Pillon, Zierath, Hulton, Drust and Sharples.

PY - 2021/2/19

Y1 - 2021/2/19

N2 - 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-α) 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.

AB - 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-α) 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.

KW - AMPK

KW - change of direction

KW - DNA methylation

KW - MAPK

KW - NR4A1 (Nur77)

KW - NR4A3

KW - PGC1 alpha

KW - VEGF

UR - http://www.scopus.com/inward/record.url?scp=85102139596&partnerID=8YFLogxK

U2 - 10.3389/fphys.2021.619447

DO - 10.3389/fphys.2021.619447

M3 - Article

AN - SCOPUS:85102139596

SN - 1664-042X

VL - 12

JO - Frontiers in Physiology

JF - Frontiers in Physiology

M1 - 619447

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this