Dear Editor-in-ChiefWhile the systemic benefits of exercise are undeniable, the precise language of inter-organ communication remains a "black box." Recent advances suggest we are poised to decode this language, transitioning from a model of diffuse hormonal signaling to one of targeted vesicular trafficking and epigenetic reprogramming. This letter posits that the next frontier for the Journal of Exercise Liu et al., 2025).Looking forward, the concept of personalized exerkine signatures presents a translational goal. Given individual variability in exerkine response, can we define an individual's "exerkine signature" to predict their metabolic or neuroprotective gains from exercise? This links the mechanistic basis of crosstalk directly to precision medicine.We therefore urge the research community to prioritize the following key questions:1. What are the exercise-intensity- and modality-dependent "sorting signals" that dictate cargo loading into EVs from distinct tissues?2. How do tissue-specific EV uptake mechanisms confer selectivity to the remote effects of exercise?3. To what extent do chronic exercise patterns establish organ-specific epigenetic "memories" via persistent metabolite signaling?By leveraging single-vesicle analyses, spatially resolved metabolomics, and cell-type-specific models, we can advance from observing crosstalk to understanding its precise syntax. Decoding this language will not only illuminate fundamental physiology but also pave the way for rationally designed, organ-specific "exercise mimetic" therapies.
Pescatello et al. (Mon,) studied this question.