Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Abstract

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex- specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and will be provided in an easily accessible public repository (https://motrpac-data.org/).

The mitochondrial multi-omic response to exercise training across tissues

“…PGC1a followed the same main trajectory, increasing in males at week 1 with a decrease in females at week 8. Interestingly, several of the known interactors of PGC1a showed the same pattern, including the PPARs 19 , Fosb, Foxo1 and Thrb (Fig. 3G).…”

“…Thermogenesis is the principal function of BAT, a tissue rich in mitochondria 70 . In contrast to females, males lost WAT-SC mass with endurance training 19 . In this context, our observed reduction in the metabolic/thermogenic activity of BAT could serve as an overall energy preservation effect in males.…”

“…This analysis takes these timewise z-scores from males and females, and uses the repfdr empirical Bayes algorithm 26 to identify the main trajectories in a selected set of tissues and omes. These are used for visualization, identifying sets of analytes that change in a specific time- and sex combination, and mitochondria-specific pathway enrichment of these sets 19 (see Methods).…”

“…All training groups started training at 6 months of age and trained on a Panlab 5-lane rat treadmill (Harvard Instruments, Model LE8710RTS). Rats were exercised 5 days per week using a progressive protocol aimed to maintain an intensity corresponding to approximately 70% of VO 2 max (increasing grade and speed, see 19 for details), with a maximal duration of 50min for the last two weeks of training. The starting treadmill speed was based on VO 2 max measurements obtained following familiarization.…”

“…Transcriptomics and metabolomics/lipidomics were conducted on all 19 tissues, while proteomics and epigenomics were performed on selected tissues only (Fig. S1A) 19 . Assay-specific details, including processing pipelines, quality control, normalization and differential analyses are summarized in Methods.…”