Just minutes of all-out sprint work produced a striking surge in circulating proteins and metabolites, revealing how exercise intensity may reshape communication between muscle, fat, and other organs.
Study: Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans. Image Credit: baranq / Shutterstock
A human exercise intervention study, available as an article in press in the journal Cell Reports Medicine, found that exercise intensity distinctly alters circulating proteins and metabolites associated with predicted inter-organ communication. The responses differed between sprint-interval exercise (SIE) and moderate-intensity exercise (MIE). The findings provide insights into how exercise intensity may influence cardiometabolic health by altering interorgan crosstalk.
Background
Exercise is key to the treatment of several cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. With regular exercise, multiple tissues and organs respond in a coordinated fashion. However, the circulating factors that mediate this crosstalk and contribute to exercise adaptations remain poorly understood.
Prior research has demonstrated changes in exerkines, including increases in secretory factors during exercise and decreases in the levels of harmful molecules. Together, these make up the exercise-induced secretome that regulates multiple metabolic pathways. These ultimately contribute to adaptations such as adipose tissue remodeling, improved whole-body glucose handling, and cognitive changes via neurogenesis and reduced neuroinflammation.
Different exercise intensities, such as sprint-interval exercise (SIE) or moderate-intensity exercise (MIE), may result in varying whole-body adaptation. This might be mediated in part by the exercise-related secretome.
For instance, N-lactoyl-phenylalanine (Lac-Phe) is an intensity-dependent, post-exercise-secreted molecule that mitigates obesity.
Previous studies suggest that SIE lasting less than five minutes often induces metabolic adaptations similar to or better than those from MIE or low-intensity exercise over longer durations.
The current study therefore investigated whether different exercise intensities produce distinct changes in the circulating proteome and metabolome, and their associations with exercise-related adaptations and cardiometabolic health.
Study design
The researchers conducted a multi-cohort human exercise intervention involving young, active, metabolically healthy participants assessed before and after training. Participants performed a single session of either sprint-interval exercise (SIE) or moderate-intensity exercise (MIE) before and after eight weeks of training, thus forming comparable pre-training and post-training groups.
In the principal cycling comparison, nine participants performed 90 minutes of MIE, while 10 completed six 30-second all-out SIE bouts separated by four-minute rests. The main cohort was male, and a subset of participants completed the eight-week training intervention.
The investigators analyzed changes in circulating proteins and metabolites associated with the different exercise conditions. They also predicted the tissues of origin and destination of exercise-regulated circulating proteins by combining this data with multi-organ gene and protein expression datasets and tissue sampling.
The study additionally examined associations between exercise-responsive circulating proteins and cardiometabolic health using a large-scale plasma-phenome database.
Exercise intensity affects the plasma proteome
The findings showed that SIE and MIE had markedly different effects on the plasma proteome. With SIE, almost a quarter of the 2,884 detected proteins showed an immediate change. This included proteins known to respond to exercise, such as growth hormone 1 (GH1).
In contrast, only seven proteins were altered from baseline after MIE. At three hours post-SIE, there was an approximately 20-fold decrease in the number of regulated proteins, while MIE-related proteins increased to 19.
Despite the small number of MIE-regulated proteins, these included established endocrine factors such as ANGPTL4, follistatin, and insulin-like growth factor-binding protein 1 (IGFBP1). The scientists suggest that these MIE changes might indicate the sustained energetic demands of continuous exercise, including an increased glucagon-to-insulin ratio and liver glycogen depletion, which can stimulate hepatic secretion of FST and IGFBP1.
Some secreted proteins, such as GH1 and NAD-kinase, rose immediately after either type of exercise, while others, such as prolactin, decreased 3 hours after exercise.
Overall, 280 proteins were differentially influenced by SIE versus MIE immediately after exercise. Most of them increased after SIE relative to MIE. Only two proteins showed a significant intensity-by-time difference at 3 hours, both of which were higher after MIE.
Further untargeted mass spectrometry supported these findings.
Notably, similar temporal patterns persisted in trained participants: a delayed rise after MIE versus an acute rise in plasma proteins after SIE, affecting many common components of the proteome.
These findings suggest an exercise-related molecular response that depends strongly on exercise intensity, although the protocols also differed substantially in duration.
Exercise intensity affects the plasma metabolome
Similar to the plasma proteome responses, the researchers found significant acute changes in 203 metabolites after SIE, including lactate, succinate, malate, pyruvate, and Lac-Phe. In addition, the metabolite kynurenic acid, which is secreted from skeletal muscle and acts on adipose tissue, increased after SIE.
At 3 hours, 199 metabolites showed significantly altered levels, including fatty acids. The authors suggest that this might indicate increasing lipid metabolism during muscle recovery.
As before, MIE showed modest acute changes, with 31 metabolites changing immediately and some fatty acids rising more than with SIE. The delayed MIE response implicated 183 metabolites.
Among metabolites that differed significantly between exercise intensities immediately after exercise, nearly all were higher after SIE than MIE, the profile suggesting increased activity in glycolytic and tricarboxylic acid (TCA) cycles with higher ATP turnover.
As with the plasma proteome, many of these changes persisted after training.
The authors suggest that “the delayed increase in plasma proteins and fatty acids after MIE likely reflects both intensity-dependent and duration-dependent changes to the secretome.” However, these could not be disentangled in this study.
Multiple organs predicted to be involved in plasma proteome changes
Using gene and protein enrichment datasets from multiple organs, the researchers found that different exercise intensities were associated with distinct protein patterns that could originate in specific tissues and potentially act on other organs.
Post-exercise changes primarily affected immune-related proteins for both exercise types. However, after MIE, there was a broader distribution of organ-enriched proteins at 3 hours, though only IGFBP1 remained differentially enriched after accounting for the intensity-by-time interaction.
SIE may acutely stimulate protein secretion from skeletal muscle
When the investigators assessed skeletal muscle gene expression after exercise, they found 30 genes predicted to encode secretory proteins that were SIE-specific and 59 that were MIE-specific, with 81 shared between the exercise intensities. Many of these encoded established exerkines.
The researchers then identified a subset of the corresponding proteins in conditioned media from human skeletal muscle cells. Mouse myotube stimulation in culture further supported intensity-dependent protein release, with simulated SIE producing substantially more differentially released proteins than simulated MIE.
This suggests that circulating proteins from skeletal muscle may appear more prominently after very high-intensity exercise, though the evidence remains inferential and future validation is essential. The authors also note that simulated SIE can increase cell damage and cytosolic protein release in vitro.
SIE strongly alters adipocyte gene expression
Similar to skeletal muscle, adipocytes appeared particularly sensitive to exercise intensity. The authors found evidence of multiple pairs of predicted differentially regulated ligands and receptors in the acute post-SIE phase.
These involved predicted signaling to the brain, immune cells, adrenals, intestine, and kidney, indicating widespread acute potential crosstalk following exercise. This activity persisted, though less strongly, at 3 hours.
Conversely, no MIE-specific pairs were identified, though the authors attribute this to their methodology and stringent inclusion criteria.
Further, extensive transcriptomic changes occurred in adipocytes treated with SIE plasma, with 1,128 and 549 genes being, respectively, upregulated and downregulated. Only 14 genes were upregulated and 11 downregulated with MIE plasma, with most also changing after SIE.
These findings were further examined using adipose tissue collected before and after a separate maximal graded treadmill exercise test.
Comparing the in vitro and intact adipose tissue datasets, the researchers found 418 differentially expressed genes shared between SIE-treated adipocytes and exercised human adipose tissue.
This suggests that adipose tissue is a target organ that may respond selectively to the post-exercise plasma environment, although the intact-tissue experiment did not directly compare SIE with MIE.
Association of intensity-dependent proteins with cardiometabolic health
Using a large plasma-phenome database, the researchers also identified 33 circulating proteins associated with a lower risk of metabolic disorders, obesity, or type 2 diabetes. These proteins changed in concentration following SIE, either acutely or at 3 hours, with 32 of the 33 regulated by SIE and three by MIE. Over a quarter of them were negatively linked to age.
These observations further highlight the potential for short episodes of SIE to induce whole-body metabolic changes, with SIE preferentially altering proteins independently associated with lower cardiometabolic disease risk. However, the analysis does not establish that the acute protein changes themselves prevent disease.
Limitations
The cohort was small and mostly male, limiting generalizability. The authors could not determine the organs of origin or destination for the metabolomic changes, while protein origins and targets were largely predicted rather than directly traced.
The SIE and MIE protocols also differed substantially in duration, preventing the researchers from fully separating intensity-dependent from duration-dependent effects. In addition, some of the skeletal muscle evidence came from in vitro models and remains inferential.
Conclusion
The study demonstrates that exercise intensity is an important determinant of changes in circulating signaling molecules, including proteins and metabolites, during and after exercise.
The findings also highlight skeletal muscle and adipose tissue as a potential source and target organ, respectively, of exercise-regulated circulating factors. By connecting these molecular changes with large-scale phenome data, the study outlines potential associations with cardiometabolic health and disease while identifying molecular pathways that may contribute to the distinct effects of different exercise intensities.
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