Muscle tissue is metabolically active to a degree perhaps not fully appreciated in past years. An only partially explored class of signals known as exerkines are generated by muscle tissue in response to physical activity and produce beneficial outcomes to cell behavior and tissue function throughout the body. Much of the signaling that passes between cells is carried by extracellular vesicles, membrane-wrapped packages of molecules of various sorts. As we enter an era in which extracellular vesicles are harvested from donors and cell cultures to be used as a basis for therapies, in much the same way as stem cells have been used, there is an increasing interest in muscle cells as a source of potentially therapeutic extracellular vesicles.
In recent years, a paradigm shift has occurred in the understanding of intercellular communication, moving beyond soluble factors (e.g., myokines) to embrace the critical role of extracellular vesicles (EVs). Among these, exosomes, small lipid-bilayer vesicles (30-150 nm) derived from the endosomal pathway, have emerged as powerful mediators of both localized and long-distance cellular crosstalk. These nanovesicles, which contain a diverse and specific cargo of proteins, lipids, and nucleic acids, are increasingly recognized as "fingerprints" of their originating cells, reflecting their metabolic and physiological state. The confluence of these fields - exercise physiology, exosome biology, and muscle pathology - has given rise to the "exerkine" hypothesis, which posits that the systemic benefits of exercise are, in part, mediated by the modulation of exosomal cargo.
This review will integrates the current evidence supporting this hypothesis, exploring the mechanisms by which exercise-induced exosomes influence muscle health, detailing their role in inter-tissue communication, and critically evaluating their potential as therapeutic tools and biomarkers. Importantly, the circulating EV pool induced by exercise is heterogeneous and originates from multiple tissues and cell types (e.g., skeletal muscle, adipose tissue, endothelium, immune cells, platelets), each contributing distinct cargo signatures and biological effects. Moreover, the physiological impact of a given exosome is not determined solely by its source cargo, but also by the recipient tissue's state (e.g., aging, inflammation, insulin resistance), which shapes uptake, signaling competence, and downstream transcriptional responses.
In this review we detail how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks.
Link: https://doi.org/10.3389/fcell.2026.1706977
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