Global multi-omics analysis of exerkines in progressive treadmill-exercised rodents

Exercise is widely recognized for its comprehensive physiological benefits, attributed largely to the secretion of signaling molecules known as exerkines. These molecules, originating from various tissues like muscles, brain, and liver, facilitate inter-organ communication and enhance metabolic health, immune function, and tissue repair. However, the responsiveness of multiple tissues and exerkines to the same exercise regimen remains poorly understood. To address this issue and elucidate patterns of time-dependent, intensity-related and sex-dimorphic tissue and exerkine responsiveness, we leveraged the publicly available Molecular Transducers of Physical Activity Consortium (MoTrPAC) dataset. Male and female Fischer 344 rats aged 6 months underwent a progressive treadmill training protocol designed to emulate human endurance exercise. Blood (cells and plasma) and 18 solid tissues such as adipose, skeletal muscle and brain were collected and multi-omics analyses, including proteomics and transcriptomics were performed on them. We examined the distribution of 26 known and 2 speculative exerkines across 2 biofluids and 18 solid tissues. Our analysis reveals that brown adipose tissue (BAT), the adrenal gland, and white adipose tissue (WAT) are the most responsive to exercise-induced changes. Fractalkine was the most responsive exerkine, followed by prosaposin (speculative), cathepsin B, and FNDC5/irisin, platelet factor 4, Clusterin and SPARC. Additionally, we found distinct patterns in the responsiveness of tissues and exerkines based on the duration and intensity of exercise, with notable differences between male and female rodents. Future research should investigate whether our findings on tissue exerkine responsiveness vary with age and disease status, and determine if these findings can be extrapolated to human populations.