Macrophages on the run: Exercise balances macrophage polarization for improved health

Objective

Exercise plays a crucial role in maintaining and improving human health. However, the precise molecular mechanisms that govern the body’s response to exercise or/compared to periods of inactivity remain elusive. Current evidence appears to suggest that exercise exerts a seemingly dual influence on macrophage polarization states, inducing both pro-immune response M1 activation and cell-repair-focused M2 activation. To reconcile this apparent paradox, we leveraged a comprehensive meta-analysis of 75 diverse exercise and immobilization published datasets (7000+ samples), encompassing various exercise modalities, sampling techniques, and species.

Methods

75 exercise and immobilization expression datasets were identified and processed for analysis. The data was analyzed using boolean relationships which uses binary gene expression relationships in order to increase the signal to noise achieved from the data, allowing for the use of comparison across such a diverse set of datasets. We utilized a boolean relationship-aided macrophage gene model [1], to model the macrophage polarization state in pre and post exercise samples in both immediate exercise and long term training.

Results

Our modeling uncovered a key temporal dynamic: exercise triggers an immediate M1 surge, while long term training transitions to sustained M2 activation. These patterns were consistent across different species (human vs mouse), sampling methods (blood vs muscle biopsy), and exercise type (resistance vs endurance), and routinely showed statistically significant results. Immobilization was shown to have the opposite effect of exercise by triggering an immediate M2 activation. Individual characteristics like gender, exercise intensity and age were found to impact the degree of polarization without changing the overall patterns. To model macrophages within the specific context of muscle tissue, we identified a focused gene set signature of muscle resident macrophage polarization, allowing for the precise measurement of macrophage activity in response to exercise within the muscle.

Conclusions

These consistent patterns across all 75 examined studies suggest that the long term health benefits of exercise stem from its ability to orchestrate a balanced and temporally-regulated interplay between pro-immune response (M1) and reparative macrophage activity (M2). Similarly, it suggests that an imbalance between pro-immune and cell repair responses could facilitate disease development. Our findings shed light on the intricate molecular choreography behind exercise-induced health benefits with a particular insight on its effect on the macrophages within the muscle.