Journal of Exercise & Organ Cross Talk

Abstract Dear Editor-in-Chief
What if the therapeutic benefits of exercise could be captured, concentrated, and delivered as a targeted molecular dose? New research on exercise-induced extracellular vesicles (ExEVs) suggests that this concept is evolving from a metaphorical understanding to a mechanistic one. Extracellular vesicles (EVs), particularly exosomes, are increasingly recognized as important facilitators of the signals generated by exercise, known as exerkines. These vesicles carry well-known myokines like IL-6 and irisin, as well as a wide range of other components, including microRNAs (miRNAs), mitochondrial DNA (mtDNA), and metabolites. This cargo is transported to distant organs, enhancing communication between muscles and various systems, including the brain, liver, and cardiovascular system (Magliulo et al., 2022; Nederveen et al., 2021).
Both aerobic and resistance training lead to a substantial increase in the secretion of extracellular vesicles (EVs) from skeletal muscle tissue, as well as a modification of their miRNA profiles, including miR-181a-5p, miR-486-5p, and miR-342-5p. These miRNAs are correlated with enhanced insulin sensitivity, reduced systemic inflammation, and neuronal protection. Consequently, this evidence underscores the role of EVs as stable carriers of exerkines that are less susceptible to enzymatic degradation and capable of delivering them more precisely than free myokines (Li et al., 2026; Silvestri et al., 2026; Wang et al., 2026).
One of the most compelling pieces of translational evidence comes from animal studies. When extracellular vesicles (ExEVs) from trained mice are injected into models of muscle disuse, they effectively preserve muscle mass and enhance regeneration (Fliflet et al., 2026). This serves as a strong proof-of-concept for developing exercise- mimetic therapeutics that can work without the need for actual exercise. In human studies, the profiles of extracellular vesicles following exercise are similarly associated with improved metabolic function and decreased markers of biological aging (Plaza-Florido et al., 2024).
Ongoing methodological obstacles, particularly in the standardization of extracellular vesicle (EV) isolation techniques, such as ultracentrifugation compared to size-exclusion chromatography, as well as in the accurate identification of their sources, whether from muscle, endothelial cells, or platelets. We propose that forthcoming investigations should progress beyond these unresolved issues towards a definitive roadmap: a multi-omics profiling approach—encompassing transcriptomics, proteomics, and lipidomics—of extracellular vesicles (ExEVs) across various exercise modalities (high-intensity interval training versus endurance training), while systematically considering sex-specific responses and age-stratified cohorts ranging from adolescence to older age. This framework would establish the groundwork for the development of vesicle-based "exercise pharmacology" (Nederveen et al., 2021).
This pioneering area not only advances our understanding of the molecular underpinnings of how exercise imparts its benefits, but also establishes a groundbreaking trajectory for therapeutics centered on extracellular vesicles—exosome mimetics formulated to treat obesity, type 2 diabetes, and sarcopenia independently of physical activity. Such developments could significantly reshape the notion of exercise prescription in medical practice.
Given the substantial transformative potential of this field, we recommend that your journal launch a special issue or thematic series on "Exercise-Derived Extracellular Vesicles in Precision Medicine." This initiative would integrate mechanistic, translational, and clinical research to fortify this swiftly evolving sector and delineate its future pathways. We believe that this Letter will be of great interest to your audience and look forward to your thoughtful consideration.

Abstract Dear Editor-in-Chief
While 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 & Organ Cross Talk lies in elucidating the rules of cargo loading, addressing, and delivery within exercise-induced extracellular vesicles‒a process likely fundamental to the remarkable specificity of organ crosstalk.
This topic moves beyond cataloguing exerkines to interrogate the mechanisms of their targeted delivery and organ-specific effects. The most compelling frontier is understanding how exercise governs the packaging, release, and uptake of extracellular vesicles, including exosomes, which function as discrete signaling packets between organs. This intersects powerfully with metabolomics and epigenetics, bearing profound implications for metabolic disease, cancer, and neurodegeneration.
First, the paradigm is shifting from humoral to vesicular signaling. The field is moving beyond viewing exerkines as freely circulating factors to recognizing their active encapsulation into extracellular vesicles (EVs). These vesicles protect their cargo, enable tissue tropism (e.g., liver-derived EVs homing to adipose tissue or brain), and deliver diverse cargo‒proteins, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and metabolites. This mechanism explains specificity in organ crosstalk previously attributed to stochastic distribution (Vechetti Jr et al., 2021).
Second, regarding the "exercise metabolome" and organ reprogramming, focus has turned to exercise-induced metabolites (e.g, lactate, succinate) which serve as potent signaling molecules. A cutting-edge perspective is how these metabolites act as histone modifiers (e.g., via lactylation) in remote organs, directly altering gene expression in the liver, brain, and immune system to mediate long-term adaptive crosstalk (Xiao et al., 2025).
Third, the gut-muscle-brain axis represents a critical microbiome-mediated highway. Exercise modulates gut microbiota composition, which subsequently produces metabolites (e.g., short-chain fatty acids (SCFAs), bile acids) that signal to both muscle, enhancing anabolic processes, and brain, modulating neurogenesis and brain-derived neurotrophic factor (BDNF) expression. This tripartite axis is a major, yet underexplored, vector in systemic communication (Frampton et al., 2020; 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.