Multi-Omic, Multi-Tissue Response to Acute Exercise in Human Cohort

Introduction: Exercise is critical to cardiovascular health. However, the underlying molecular mechanisms are not well described. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) seeks to create a detailed molecular map of the response to exercise. Described here is the first human cohort of MoTrPAC, enrolled prior to the COVID-19 shutdown (N=175). Methods: Healthy, sedentary adults were randomized to an 8-exercise circuit of resistance exercise (RE, N=73), a 40 minute submaximal endurance exercise bout (EE, N=65), or to non-exercising control (N=37). Blood, muscle, and adipose tissue were sampled at 4-7 time points relative to exercise, depending on tissue/modality. Samples were deep phenotyped across multiple omic domains including chromatin accessibility, transcriptomics, proteomics, phosphoproteomics, and metabolomics. Results: The cohort was 72% female, with a mean±sd age of 41±15 years and BMI of 27.1±4.0 kg/m2. Exercise affected over 34,000 molecular features in ≥1 tissue/time point including a high proportion of transcriptomic and phosphoproteomic features (Figure A). Molecular signatures were compared between EE and RE: enrichment analysis of muscle phosphoproteomics showed a greater activation of MAP kinases in RE compared to EE at all time points. To identify plausible exerkines (secreted molecules signaling an acute exercise bout), differentially abundant features in any sampled tissue cells were compared to temporally-matched cognate protein levels in plasma, yielding 110 features. A known exerkine, CX3CL1 (fractalkine) was identified, in addition to novel candidates, such as cellular communication network factor 1 (CCN1), a secreted extracellular matrix protein linked to plasma triglyceride levels, which showed increased abundance early post exercise (Figure B). Network analysis across tissues and omes identified novel transcription factor “hubs” as candidate master regulators of exercise response. Conclusions: These first MoTrPAC data represent an unparalleled multi-tissue, multi-omic, multi-time point, multi-modality map of acute exercise, enhancing our understanding of the molecular transducers that may link exercise and cardiovascular health.