RPLP2 Mediates the Beneficial Effects of Exercise on Stress Resistance Through Muscle–Brain Communication

ABSTRACT Anxiety disorders pose a considerable burden on public health. While exercise has been increasingly established as a viable strategy for preventing and alleviating anxiety symptoms, the underlying molecular mechanisms of this action remain elusive. We previously conducted an 8‐week randomized controlled trial which suggested that exercise not only significantly reduced anxiety levels but also triggered the release of acidic ribosomal protein P2 (RPLP2) from peripheral tissues into the bloodstream. These elevated circulating RPLP2 levels showed an inverse association with anxiety severity in patients, suggesting a potential therapeutic role for the protein. Further experiments in mice confirmed that skeletal muscle–derived RPLP2 exerts its anxiolytic effects by facilitating hippocampal neurogenesis. Mechanistically, RPLP2 facilitates ribosomal localization and increases the efficiency of ribosomal subunit assembly, thereby increasing local protein synthesis and supporting the development and maturation of newly generated neurons. The successful maturation of these neurons, in turn, promotes morphological and functional synaptic plasticity, which is crucial for the integration and functional maturation of newborn neurons into hippocampal circuits. Collectively, our findings reveal a previously unknown muscle–brain axis mediated by RPLP2, offering mechanistic evidence for exercise‐induced stress resistance.