Abstract 4367452: Integrated Multi-omics Analysis of Skeletal Muscle in Response to a Bout of Resistance or Endurance Exercise

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Introduction: The Molecular Transducers of Physical Exercise Consortium (MoTrPAC) was established to characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response to acute endurance and resistance exercise in data derived from skeletal muscle biopsies from human participants. Methods: Sedentary participants (n=174) were randomized into endurance exercise (EE, N=64), resistance exercise (RE, N=73) or control (CON, N=37) groups. Vastus lateralis muscle biopsies were collected before a sub-maximal acute bout of either EE or RE (or CON) and at several time points after following the bout (15min, 3.5h, and 24h). Muscle biopsies were analyzed by ATACseq, RNA-seq, proteomics, phosphoproteomics, and metabolomics. Differentially abundant features at each time point were selected using false discrovery rate of 5%. Results: Multi-omics analyses revealed distinct temporal responses across omes. Maximal changes in ATAC-seq, phosphoproteome, and metabolome occurred earlier (15 min) than transcriptome and proteome changes (3.5h and 24h). Differences in the magnitude of changes were significant, with RE resulting in more altered features. Integrated multi-omics revealed early changes in differentially accessible regions (DARs; ATAC-seq) followed by mid- to late changes (3.5h and 24h) in gene and protein expression for EE and RE, suggesting temporal coordination between chromatin remodeling and gene/protein expression post-exercise. Pathway enrichment highlighted ribosomal biology and mesenchymal skeletal muscle stem cells in RE and cristae formation and mitofission at 24h in EE. Both modalities upregulated angiogenesis and VEGFR2 signaling at 15 min; this signal remained enriched 3.5h after RE but not EE. PTM analysis indicated early kinase signature enrichment, more pronounced and prolonged in RE, notably in MAPK activation. Novel findings include the downregulation of HIPK2 and HIPK3 kinase signatures, including the phosphotyrosine Y359 in HIPK3's activation loop. The leading edges of the HIPK3 signature featured two phosphosites (S173 and T285) of BAG3 as the most downregulated in both modalities, implicating the HIPK/BAG3 axis in signaling for skeletal muscle response to acute exercise. Conclusions: These MoTrPAC data provide key insights into the multi-omic exercise responses in skeletal muscle and highlight EE and RE specific effects on biological pathways.

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