Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Sarah Voisin; Kirsten Seale; Macsue Jacques; Shanie Landen; Nicholas R. Harvey; Larisa M. Haupt; Lyn R. Griffiths; Kevin J. Ashton; Vernon G. Coffey; Jamie Lee M. Thompson; Thomas M. Doering; Malene E. Lindholm; Colum Walsh; Gareth Davison; Rachelle Irwin; Catherine McBride; Ola Hansson; Olof Asplund; Aino E. Heikkinen; Päivi Piirilä; Kirsi H. Pietiläinen; Miina Ollikainen; Sara Blocquiaux; Martine Thomis; Coletta K. Dawn; Adam P. Sharples; Nir Eynon

doi:10.1111/acel.13859

Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle

Sarah Voisin^*
, Kirsten Seale
, Macsue Jacques
, Shanie Landen
, Nicholas R. Harvey
, Larisa M. Haupt
, Lyn R. Griffiths
, Kevin J. Ashton
, Vernon G. Coffey
, Jamie Lee M. Thompson
, Thomas M. Doering
, Malene E. Lindholm
, Colum Walsh
, Gareth Davison
, Rachelle Irwin
, Catherine McBride
, Ola Hansson
, Olof Asplund
, Aino E. Heikkinen
, Päivi Piirilä

Kirsi H. Pietiläinen, Miina Ollikainen, Sara Blocquiaux, Martine Thomis, Coletta K. Dawn, Adam P. Sharples, Nir Eynon^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late- life exercise mitigates epi -genetic 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 samples (n= 3176). We show that: (1) individuals with higher baseline aero -bic 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 struc-ture, 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.

Originalsprog	Engelsk
Artikelnummer	e13859
Tidsskrift	Aging Cell
Vol/bind	23
Udgave nummer	1
Antal sider	15
ISSN	1474-9718
DOI	https://doi.org/10.1111/acel.13859
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by Sarah Voisin's National Health & Medical Research Council (NHMRC) Early Career Research Fellowship (APP11577321) and by Nir Eynon's NHMRC Career Development Fellowship (APP1140644). The Gene SMART and LITER studies were both supported by the Collaborative Research Network for Advancing Exercise and Sports Science (201202) scheme awarded to VGC and KJA from the Department of Education and Training, Australia. Mr Nicholas Harvey was supported by a Ph.D. stipend also provided by Bond University CRN‐AESS. This research was also supported by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia – Queensland Node project (LRG). Work at Ulster was supported by an Interdisciplinary Award. We also greatly acknowledge Erika Guzman at the ATGC/IHBI/QUT for performing the HMEPIC assays in the LITER study. The EPIK study was supported by the Research Foundation Flanders (FWO G.0898.15). Open access publishing facilitated by Victoria University, as part of the Wiley ‐ Victoria University agreement via the Council of Australian University Librarians.

Publisher Copyright:
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Finansiering

This work was supported by Sarah Voisin's National Health & Medical Research Council (NHMRC) Early Career Research Fellowship (APP11577321) and by Nir Eynon's NHMRC Career Development Fellowship (APP1140644). The Gene SMART and LITER studies were both supported by the Collaborative Research Network for Advancing Exercise and Sports Science (201202) scheme awarded to VGC and KJA from the Department of Education and Training, Australia. Mr Nicholas Harvey was supported by a Ph.D. stipend also provided by Bond University CRN‐AESS. This research was also supported by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia – Queensland Node project (LRG). Work at Ulster was supported by an Interdisciplinary Award. We also greatly acknowledge Erika Guzman at the ATGC/IHBI/QUT for performing the HMEPIC assays in the LITER study. The EPIK study was supported by the Research Foundation Flanders (FWO G.0898.15). Open access publishing facilitated by Victoria University, as part of the Wiley ‐ Victoria University agreement via the Council of Australian University Librarians.

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Citationsformater

Voisin, S., Seale, K., Jacques, M., Landen, S., Harvey, N. R., Haupt, L. M., Griffiths, L. R., Ashton, K. J., Coffey, V. G., Thompson, J. L. M., Doering, T. M., Lindholm, M. E., Walsh, C., Davison, G., Irwin, R., McBride, C., Hansson, O., Asplund, O., Heikkinen, A. E., ... Eynon, N. (2024). Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle. Aging Cell, 23(1), Artikel e13859. https://doi.org/10.1111/acel.13859

Voisin, S, Seale, K, Jacques, M, Landen, S, Harvey, NR, Haupt, LM, Griffiths, LR, Ashton, KJ, Coffey, VG, Thompson, JLM, Doering, TM, Lindholm, ME, Walsh, C, Davison, G, Irwin, R, McBride, C, Hansson, O, Asplund, O, Heikkinen, AE, Piirilä, P, Pietiläinen, KH, Ollikainen, M, Blocquiaux, S, Thomis, M, Dawn, CK, Sharples, AP & Eynon, N 2024, 'Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle', Aging Cell, bind 23, nr. 1, e13859. https://doi.org/10.1111/acel.13859

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title = "Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle",

abstract = "Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late- life exercise mitigates epi -genetic 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 samples (n= 3176). We show that: (1) individuals with higher baseline aero -bic 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 {\textquotedblleft}ages{\textquotedblright} 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 struc-ture, 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.",

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year = "2024",

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AU - Voisin, Sarah

AU - Seale, Kirsten

AU - Jacques, Macsue

AU - Landen, Shanie

AU - Harvey, Nicholas R.

AU - Haupt, Larisa M.

AU - Griffiths, Lyn R.

AU - Ashton, Kevin J.

AU - Coffey, Vernon G.

AU - Thompson, Jamie Lee M.

AU - Doering, Thomas M.

AU - Lindholm, Malene E.

AU - Walsh, Colum

AU - Davison, Gareth

AU - Irwin, Rachelle

AU - McBride, Catherine

AU - Hansson, Ola

AU - Asplund, Olof

AU - Heikkinen, Aino E.

AU - Piirilä, Päivi

AU - Pietiläinen, Kirsi H.

AU - Ollikainen, Miina

AU - Blocquiaux, Sara

AU - Thomis, Martine

AU - Dawn, Coletta K.

AU - Sharples, Adam P.

AU - Eynon, Nir

PY - 2024

Y1 - 2024

N2 - Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late- life exercise mitigates epi -genetic 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 samples (n= 3176). We show that: (1) individuals with higher baseline aero -bic 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 struc-ture, 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.

AB - Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late- life exercise mitigates epi -genetic 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 samples (n= 3176). We show that: (1) individuals with higher baseline aero -bic 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 struc-ture, 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.

KW - aging

KW - cardiorespiratory fitness

KW - DNA methylation

KW - exercise training

KW - human skeletal muscle

KW - meta-analysis

KW - mRNA expression

U2 - 10.1111/acel.13859

DO - 10.1111/acel.13859

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JO - Aging Cell

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