Background Cancer, cardiovascular diseases (CVD), and type 2 diabetes (T2D) may co-occur, a condition referred to as multimorbidity. Physical activity is inversely associated with each of these diseases; however, the biologic pathways underlying these relationships remain incompletely understood.

Methods In 33,806 UK Biobank participants, we derived a proteomic signature (high-throughput panel of 2,911 proteins assessed by Olink array) of moderate-to-vigorous physical activity using linear and LASSO regressions in a two-step procedure to prospectively assess associations with physical activity-related cancers (1,108 cases), CVD (3,445 cases), T2D (1,363 cases), as well as progression to multimorbidity (420 cases). Multivariable Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each identified protein, as well as their linear combination (proteomics signature score), separately for each outcome and with adjustment for physical activity. Pathway enrichment analysis and protein-protein interaction networks were used to gain insights into the systemic interplay of the identified proteins.

Results After correction for multiple testing, 223 proteins were selected in the physical activity signature. Proteins involved in food intake, metabolism, and cell growth regulation (e.g., LEP, MSTN, TGFBR2) were inversely associated with physical activity. Proteins involved in immune cell adhesion and migration, as well as cartilage and muscle integrity (e.g., integrins, COMP, MYOM3) were positively associated with physical activity. Several proteins upregulated by physical activity were inversely associated with disease risk (e.g., integrins, PI3, CLEC4A for cancer risk, or LPL, IGFBP1, LEP for T2D risk). Similarly, various proteins were downregulated by physical activity and positively associated with disease risk (e.g., CD38, TGFA for CVD risk). For multimorbidity, proteins inversely related to physical activity generally aligned with expected risk patterns, while positively associated proteins exhibited mixed effects, with inverse and positive associations. The proteomics signature score was inversely associated with the risk of cancer (HR per interquartile range: 0.87; 95% CI: 0.78, 0.96) and T2D (HR: 0.66; 95% CI: 0.60, 0.72), after adjustment for physical activity, but not with CVD (HR: 0.93; 95% CI: 0.85, 1.03) and progression towards multimorbidity.

Conclusions These findings suggest that the inverse relationships between physical activity and risk of major chronic diseases may be explained by the maintenance of tissue integrity and the proper regulation of immune and metabolic processes. Further studies are needed to determine the causal nature of these associations.

The authors have declared no competing interest.

Funding for IIG_FULL_2021_027 was obtained from World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme. This study was supported by the French National Cancer Institute (l'Institut National du Cancer, INCA_16824), the German Research Foundation (BA 5459/2-1). The UK Biobank was supported by the Wellcome Trust, Medical Research Council, Department of Health, Scottish government, and Northwest Regional Development Agency. It has also had funding from the Welsh Assembly government and British Heart Foundation. The research was designed, conducted, analysed, and interpreted by the authors entirely independently of these funding sources. The funder had no role in study design, data acquisition and analysis, decision to publish, or preparation of the manuscript.

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Ethical approval was obtained from the North West Multi-Centre Research Ethics Committee (21/NW/0157).

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