Different patterns of physical activity (PA), including sedentary behavior, have been linked to a wide range of health outcomes. However, the underlying molecular mechanisms— particularly the biological pathways connecting distinct aspects of PA to health outcomes—are incompletely understood. In this study, we investigated the associations between 14 PA features across four categories—captured using wearable accelerometer data—and plasma protein (PP) expression levels in 9,210 individuals from the UK Biobank. Our analysis identified 2,655 significantly associated PA feature–PP expression pairs, involving 613 unique proteins. These included broadly associated proteins such as ITGAV and MYOM3, which were linked to all PA feature categories, as well as proteins uniquely associated with specific activity features. Mediation analysis revealed 359 paths linking 10 PA features, 99 unique PPs, and seven incident health outcomes. Aggressive PA features, including both the proportion of moderate-to-vigorous physical activity (MVPA) time and the frequency of MVPA bouts, exhibited protective effects mediated through proteins to those risks for incident health outcomes. Proteins such as GDF15, PRSS8, and IGFBP4 mediated associations across multiple PA features. Additionally, genetic analyses identified 32 mediator proteins with putative causal effects on incident health outcomes, highlighting them as potential therapeutic targets. Together, these results implicate PP as key mediators of the health effects of PA, offering new mechanistic insights and uncovering potential targets for therapeutic intervention.

The authors have declared no competing interest.

This study utilized data from the UK Biobank resource under application numbers 197947. We sincerely thank the participants and staff of the UK Biobank for the invaluable contributions. M.W., H.Q., and Y.Y were supported by M.W.s startup fund from the Institute of Heart and Brain Health. This work was supported by grants the NIH R35 HL155318 to A.R. and the American Heart Association (AHA) grants 23MERIT1038415 to A.R. and SFRN (URLs: https://doi.org/10.58275/ AHA.24SFRNPCN1284382.pc.gr.194135 and https://doi.org/10.58275/ AHA.24SFRNCCN1276092.pc.gr.194131) to A.R. and M.W.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All UK Biobank data (accelerometer, demographics, proteomic) are accessible via application to the UK Biobank. PQTL summary statistics from the UKB-PPP can be accessed at https://metabolomips.org/ukbbpgwas.