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 af dette arbejde

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

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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.

Originalsprog	Engelsk
Artikelnummer	115750
Tidsskrift	Cell Reports
Vol/bind	44
Udgave nummer	6
Antal sider	20
ISSN	2639-1856
DOI	https://doi.org/10.1016/j.celrep.2025.115750
Status	Udgivet - 2025

Bibliografisk note

Publisher Copyright:
© 2025 The Author(s)

Adgang til dokumentet

10.1016/j.celrep.2025.115750Licens: CC BY

FullterxtForlagets udgivne version, 5,58 MBLicens: CC BY

Citationsformater

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), Artikel 115750. https://doi.org/10.1016/j.celrep.2025.115750

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, bind 44, nr. 6, 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 (VO2max), 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.",

keywords = "CP: Metabolism, DNA methylation, epigenetics, exercise, gene expression, Multi Omics, proteomic, skeletal muscle, transcriptomic, VO",

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",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

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

language = "English",

volume = "44",

journal = "Cell Reports",

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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

Y1 - 2025

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 (VO2max), 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 (VO2max), 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.

KW - CP: Metabolism

KW - DNA methylation

KW - epigenetics

KW - exercise

KW - gene expression

KW - Multi Omics

KW - proteomic

KW - skeletal muscle

KW - transcriptomic

KW - VO

U2 - 10.1016/j.celrep.2025.115750

DO - 10.1016/j.celrep.2025.115750

M3 - Journal article

C2 - 40445834

AN - SCOPUS:105006740608

SN - 2639-1856

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 115750

ER -