Exercise remodels the circulating extracellular particle proteome in men
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Extracellular particles (EPs), including extracellular vesicles, are emerging mediators of inter-organ communication with growing relevance to cardiometabolic health. Whereas acute exercise mobilizes EV-associated proteins into the circulation, the plasma EP-enriched proteome response to long-term exercise—and its relationship to specific metabolic adaptations—has not been characterized at scale. It also remains untested whether EP-compartment signals carry information distinct from, and not captured by, conventional bulk serum proteomics. Twenty-six men completed 12 weeks of combined strength and endurance training (MyoGlu). Plasma EP-enriched fractions were isolated using the MagNet (SAX) protocol at four timepoints: pre-training rest (A1), post-training rest after three months (B1), immediately after the final exercise bout (B2), and two hours into recovery (B3). EP proteins were quantified by untargeted mass spectrometry. Long-term exercise responses (B1 vs. A1), acute exercise responses (B2 vs. B1), and recovery responses (B3 vs. B1) were modeled using linear mixed-effects models with FDR correction. EP protein changes were integrated with matched skeletal muscle and adipose tissue transcriptomics, compared against conventional bulk-serum proteomics (Olink Explore 3072, ~ 2900 proteins), and related to cardiorespiratory fitness (VO 2 max), insulin sensitivity (M-value), body composition, and muscle strength. Long-term exercise induced significant changes in 127 of 1545 EP-enriched proteins tested (FDR < 5%), with 76 increased and 51 decreased. The increased proteins were enriched for extracellular matrix (q = 6.0 × 10 −10 ), collagen-containing extracellular matrix (q = 8.6 × 10 −7 ) and cell adhesion (q = 7.2 × 10 −4 ). EP protein changes showed phenotype-specific associations with cardiorespiratory fitness (VO 2 max), insulin sensitivity (M-value), body composition, and muscle strength—demonstrating a metabolically differentiated rather than a uniform stress response. Four EP proteins (LTBP4, VCL, MEP1B, HSP90B1) formed a coherent candidate group associated with improved VO 2 max. For the two proteins also measurable in serum (MEP1B and HSP90B1), this association was seen only in the EP-enriched fraction, though specimen, platform, and enrichment differences preclude a definitive compartment attribution. EP-associated triosephosphate isomerase 1 (TPI1) showed a nominal association with ΔM-value. Integrative multi-omics analyses implied coordinated cross-tissue remodeling, with EP proteins co-varying with skeletal muscle transcripts linked to mitochondrial biogenesis and contractile remodeling and adipose transcripts linked to lipid and ECM programs. Acute EP responders clustered into four temporal trajectory classes that overlapped 9.4% with long-term exercise-responsive proteins, which tended to move in opposite directions acutely and over 12 weeks. Long-term exercise drives broad remodeling of the plasma EP-enriched proteome tracking individual cardiometabolic adaptation, including cardiorespiratory fitness and insulin sensitivity. These findings suggest that EP transport is a regulated process relevant to cardiometabolic risk and point to novel EP biomarkers for cardiometabolic disease prevention and intervention.
Source: Cardiovascular Diabetology
Institutions: University of Oslo, Oslo University Hospital, Vitas (Norway)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,290
OpenAlex ID: W7213754340
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