A recent study published in Nature presented a whole-organism molecular map of the temporal effects of endurance training in rats.
Study: Temporal dynamics of the multi-omic response to endurance exercise training. Image Credit: Min C. Chiu/Shutterstock.com
Background
Regular exercise has several benefits, such as lower risks of cancer, neurological and cardiometabolic diseases, and all-cause mortality. Exercise affects almost all organ systems, with beneficial effects occurring due to molecular/cellular adaptations across and within tissues and organ systems.
Several omic platforms (omes), such as epigenomics, transcriptomics, metabolomics, and proteomics, have been leveraged to study these events.
Nevertheless, studies have often focused on a single tissue covering one or two omes and have been biased. A comprehensive, whole-organism, multi-omic map of exercise effects is required.
To this end, the Molecular Transducers of Physical Activity Consortium has been established to build a molecular map of responses to exercise across diverse tissues in animals and the blood, adipose tissue, and skeletal muscle in humans.
The study and findings
The present study presented an organism-wide molecular map of rats' endurance training effects/responses. First, 344 rats were subject to progressive treadmill exercise (endurance training) for one, two, four, or eight weeks. Tissues were collected 48 hours after the last training bout. Sex-matched, untrained, sedentary rats served as controls.
Training led to robust phenotypic changes, increasing aerobic capacity by 16% and 18% in female and male rats, respectively, at eight weeks.
Body fat was reduced by 5% in males at eight weeks, with no significant lean mass changes. Body fat percentage was unchanged in females after four or eight weeks of training.
Whole blood, 18 solid tissues, and plasma were analyzed using multi-omic technologies. Molecular assays were prioritized by biological relevance and (available) tissue quantity.
Overall, 9,466 assays were performed across 211 tissue combinations and molecular platforms, leading to over 0.6 million non-epigenetic and 14.3 million epigenetic measurements.
Training-regulated molecules were observed in most tissues for all omes. For transcriptomics, the vena cava, testes, cortex, and hypothalamus had the fewest training-regulated genes, while the blood, colon, adrenal gland, and adipose tissues had extensive effects.
For proteomics, the heart, liver, and gastrocnemius had substantial differential regulation in protein abundance and post-translational modifications.
For metabolomics, all tissues consistently exhibited the most differential metabolites. Next, six tissues (kidney, lung, white adipose tissue, gastrocnemius, heart, and liver) with extensive molecular profiling were selected to assess training-responsive gene expression.
Overall, 11,407 differential features were mapped for 7,115 unique genes. Around 67% of genes with ≥ one training-responsive feature were tissue-specific.
Further, 2,359 genes had differential features in ≥ two tissues, with the white adipose tissue and lungs uniquely sharing the largest gene sets, predominately immune-related. All six tissues shared 22 training-regulated genes particularly enriched in heat shock response pathways.
Hematopoiesis-related transcription factors were enriched in the blood, whereas the myocyte-enhancer factor 2 (Mef2) family transcription factor motifs were enriched in the skeletal muscle and heart.
Phosphorylation signatures of several notable kinases were altered across several tissues. Next, differential features were clustered with complete timewise summary statistics to compare multi-omic responses to training across tissues. Pathway enrichment analysis was performed for several clusters, and the biological processes associated with training were examined.
The liver had substantial chromatin accessibility regulation compared to other tissues. The blood had enrichments related to organelle biogenesis/maintenance and translation.
In the gastrocnemius, terms related to lipid synthesis/degradation and peroxisome proliferator-activated receptor (PPAR) signaling were enriched at the protein level. In contrast, those related to glycerophospholipid metabolism and ether lipid were enriched at the metabolomic level.
Notably, plasma and small intestine had more changes at one and two weeks of training. Further, sex differences in responses to training were observed in many tissues, with 58% of the training-regulated features being sex-differentiated at eight weeks.
Opposite responses between sexes were noted in lung phosphosites, liver acetylsites, and adrenal gland and white adipose tissue transcripts. Proinflammatory cytokines showed sex differences in several tissues.
A majority of female-specific cytokines showed differential regulation between weeks 1 and 2 of training. Conversely, the differential regulation of most male-specific cytokines was observed between the fourth and eighth week of training.
Further, the adrenal gland exhibited an extensive transcriptional remodeling, with over 4,000 differentially regulated genes. In the lung, phosphosignaling activity declined with training in males.
Finally, organism-wide metabolic changes were summarized. The liver, heart, lung, and hippocampus had the most enriched metabolite classes.
Further investigation into acylcarnitine groups and individual metabolites revealed changes linked to functional alterations in response to training. There was a substantial increase in cortisol levels in the kidney.
Metabolic pathways in the liver were substantially regulated across the lipidome, proteome, and acetylome, with significant enrichment in 12 metabolite classes of lipids and lipid-related compounds.
Most liver features corresponded to changes in the amino acid, mitochondrial, and lipid metabolic pathways. Phosphatidylcholines were elevated, with a concomitant reduction in triacylglycerols.
Conclusions
The study employed 25 molecular platforms in multiple tissues and reported the temporal dynamics of the endurance training response in rats. Thousands of training-responsive changes were observed across and within tissues in mRNA transcripts, proteins, and metabolites.
Many changes were relevant to human health, including cardiovascular health and tissue injury/recovery. Overall, the findings contribute to understanding exercise-related improvements in health and disease.
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