Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Macsue Jacques; Shanie Landen; Adam P. Sharples; Andrew Garnham; Ralf Schittenhelm; Joel Steele; Aino Heikkinen; Elina Sillanpää; Miina Ollikainen; James Broatch; Navabeh Zarekookandeh; Ola Hanson; Ola Ekström; Olof Asplund; Séverine Lamon; Sarah E. Alexander; Cassandra Smith; Carlie Bauer; Mary N. Woessner; Itamar Levinger; Andrew E. Teschendorff; Linn Gillberg; Ida Blom; Jørn Wulff Helge; Nicholas R. Harvey; Larisa M. Haupt; Lyn R. Griffiths; Atul S. Deshmukh; Kirsi H. Pietiläinen; Päivi Piirilä; Robert A.E. Seaborne; Marie Klevjer; Anja Bye; Ulrik Wisløff; Bernadette Jones-Freeman; Nir Eynon

doi:10.1016/j.celrep.2025.115750

Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

Macsue Jacques, Shanie Landen, Adam P. Sharples, Andrew Garnham, Ralf Schittenhelm, Joel Steele, Aino Heikkinen, Elina Sillanpää, Miina Ollikainen, James Broatch, Navabeh Zarekookandeh, Ola Hanson, Ola Ekström, Olof Asplund, Séverine Lamon, Sarah E. Alexander, Cassandra Smith, Carlie Bauer, Mary N. Woessner, Itamar LevingerAndrew E. Teschendorff, Linn Gillberg, Ida Blom, Jørn Wulff Helge, Nicholas R. Harvey, Larisa M. Haupt, Lyn R. Griffiths, Atul S. Deshmukh, Kirsi H. Pietiläinen, Päivi Piirilä, Robert A.E. Seaborne, Marie Klevjer, Anja Bye, Ulrik Wisløff, Bernadette Jones-Freeman, Nir Eynon^*

^*Corresponding author for this work

Faculty of Health Sciences & Medicine

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

Abstract

We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO 2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

Original language	English
Article number	115750
Pages (from-to)	1-21
Number of pages	21
Journal	Cell Reports
Volume	44
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2025.115750
Publication status	Published - 24 Jun 2025

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Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integrationFinal published version, 5.6 MBLicence: CC BY

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Jacques, M., Landen, S., Sharples, A. P., Garnham, A., Schittenhelm, R., Steele, J., Heikkinen, A., Sillanpää, E., Ollikainen, M., Broatch, J., Zarekookandeh, N., Hanson, O., Ekström, O., Asplund, O., Lamon, S., Alexander, S. E., Smith, C., Bauer, C., Woessner, M. N., ... Eynon, N. (2025). Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration. Cell Reports, 44(6), 1-21. Article 115750. https://doi.org/10.1016/j.celrep.2025.115750

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title = "Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration",

abstract = "We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO 2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention. ",

author = "Macsue Jacques and Shanie Landen and Sharples, {Adam P.} and Andrew Garnham and Ralf Schittenhelm and Joel Steele and Aino Heikkinen and Elina Sillanp{\"a}{\"a} and Miina Ollikainen and James Broatch and Navabeh Zarekookandeh and Ola Hanson and Ola Ekstr{\"o}m and Olof Asplund and S{\'e}verine Lamon and Alexander, {Sarah E.} and Cassandra Smith and Carlie Bauer and Woessner, {Mary N.} and Itamar Levinger and Teschendorff, {Andrew E.} and Linn Gillberg and Ida Blom and Helge, {J{\o}rn Wulff} and Harvey, {Nicholas R.} and Haupt, {Larisa M.} and Griffiths, {Lyn R.} and Deshmukh, {Atul S.} and Pietil{\"a}inen, {Kirsi H.} and P{\"a}ivi Piiril{\"a} and Seaborne, {Robert A.E.} and Marie Klevjer and Anja Bye and Ulrik Wisl{\o}ff and Bernadette Jones-Freeman and Nir Eynon",

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doi = "10.1016/j.celrep.2025.115750",

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Jacques, M, Landen, S, Sharples, AP, Garnham, A, Schittenhelm, R, Steele, J, Heikkinen, A, Sillanpää, E, Ollikainen, M, Broatch, J, Zarekookandeh, N, Hanson, O, Ekström, O, Asplund, O, Lamon, S, Alexander, SE, Smith, C, Bauer, C, Woessner, MN, Levinger, I, Teschendorff, AE, Gillberg, L, Blom, I, Helge, JW, Harvey, NR, Haupt, LM, Griffiths, LR, Deshmukh, AS, Pietiläinen, KH, Piirilä, P, Seaborne, RAE, Klevjer, M, Bye, A, Wisløff, U, Jones-Freeman, B & Eynon, N 2025, 'Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration', Cell Reports, vol. 44, no. 6, 115750, pp. 1-21. https://doi.org/10.1016/j.celrep.2025.115750

TY - JOUR

T1 - Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

AU - Jacques, Macsue

AU - Landen, Shanie

AU - Sharples, Adam P.

AU - Garnham, Andrew

AU - Schittenhelm, Ralf

AU - Steele, Joel

AU - Heikkinen, Aino

AU - Sillanpää, Elina

AU - Ollikainen, Miina

AU - Broatch, James

AU - Zarekookandeh, Navabeh

AU - Hanson, Ola

AU - Ekström, Ola

AU - Asplund, Olof

AU - Lamon, Séverine

AU - Alexander, Sarah E.

AU - Smith, Cassandra

AU - Bauer, Carlie

AU - Woessner, Mary N.

AU - Levinger, Itamar

AU - Teschendorff, Andrew E.

AU - Gillberg, Linn

AU - Blom, Ida

AU - Helge, Jørn Wulff

AU - Harvey, Nicholas R.

AU - Haupt, Larisa M.

AU - Griffiths, Lyn R.

AU - Deshmukh, Atul S.

AU - Pietiläinen, Kirsi H.

AU - Piirilä, Päivi

AU - Seaborne, Robert A.E.

AU - Klevjer, Marie

AU - Bye, Anja

AU - Wisløff, Ulrik

AU - Jones-Freeman, Bernadette

AU - Eynon, Nir

PY - 2025/6/24

Y1 - 2025/6/24

N2 - We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO 2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

AB - We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO 2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

UR - https://kclpure.kcl.ac.uk/portal/en/publications/be14b227-69d8-4f49-9112-9ae18e9ada5e

U2 - 10.1016/j.celrep.2025.115750

DO - 10.1016/j.celrep.2025.115750

M3 - Article

C2 - 40445834

SN - 2211-1247

VL - 44

SP - 1

EP - 21

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 115750

ER -

Molecular landscape of sex- and modality-specific exercise adaptation in human skeletal muscle through large-scale multi-omics integration

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