Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise

Abstract

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Figure 1.. General overview of MoTrPAC.

Preclinical Animal Study Sites (PASS) (rats) and Human Clinical Exercise Sites will collect biospecimen samples after acute and chronic exercise. The biospecimen samples will be sent to a central biorepository where they will be logged, processed and distributed to various Chemical Analysis Sites (CAS) for ‘omics analysis. A portion of the biospecimen samples will be kept at the biorepository for future ancillary study opportunities by the scientific community. Data generated from the CAS sites will be transferred to the Bioinformatics Center (BIC) for a multi-omics, multi-species, multi-tissue and multi-time point integration of the data with the goal of generating a molecular map of exercise. The data will be available to the scientific community via the MoTrPAC Data Hub: https://motrpac-data.org.

Figure 2.. A general schematic of the preclinical and clinical studies.

A) Biospecimen collection for the rat studies (N=820, including non-exercised controls) is ongoing and will be completed in Fall 2020. For both the acute (i.e. single bout; n=526) and chronic phases (i.e. training; n=294), six- and eighteen-month old male and female rats are being studied, and both exercise phases include a cohort of non-exercised controls. B) ~2600 healthy individuals will be evaluated physiologically, and biospecimens will be collected to accommodate molecular probing of various tissues before and after acute and chronic endurance or resistance exercise. For the adult cohort, the control participants will rest quietly (i.e., no exercise) during the acute bout with biospecimen collections. *Assessments include blood profile, body composition, heart health, VO₂max and strength.

Figure 3.. Overview of biospecimen collections and integrated analysis plan.

Preclinical studies: For the acute exercise arm, biospecimens (N=25 per animal) are being collected 0 (i.e., immediately post), 0.5, 1, 4, 7, 24 or 48 hours following exercise. For the chronic exercise training arm, which has been completed, biospecimens (N=28) were collected 48 hours after rats completed 1, 2, 4 or 8 weeks of treadmill training. For both study arms, the same biospecimens are being collected from an unexercised group of rats. Clinical Studies: Human biospecimens (blood, muscle, adipose; blood only for pediatrics) will be obtained before and at 0.5, 4 and 24 hours following endurance or resistance exercise. The sedentary participants will perform the acute exercise bout with biospecimen collections twice (before and after 12 weeks of training) while the highly active participants will perform this one time (see Human Clinical Sites description in the text for more detail). The ‘omics data generated from multiple different genomics, proteomics and metabolomics assays will be processed in assay-specific pipelines. Omic specific analyses followed by state-of-the-art integrative methods will be applied for a multi-omic analysis of the multiple timepoints and tissues collected in MoTrPAC with the goal of creating a map of the molecular transducers of exercise. All data (pipelines, raw and processed data, results, and integrative analyses) will be made publicly available through the MoTrPAC Data Hub: https://motrpac-data.org.

Figure 4.. Role of exosomes in integrating the exercise response across organ systems.

Exosomes are small extracellular vesicles (EVs) that are packaged with functional molecular cargo and released from most cell types. Exosomes released in response to exercise can be transported in the blood to various other tissues (adipose, brain, liver, etc.) where their contents can be released and have biological impact. Protein and miRNA cargo of circulating EVs from MoTrPAC samples will be analyzed to provide additional insight into this emerging biological phenomenon.