Extracellular Vesicle-Mediated microRNA Signaling in Osteosarcopenia: Emerging Insights into Age-Related Bone-Muscle Crosstalk.

Abstract

Osteosarcopenia combines low bone strength with sarcopenia and increases the risks of falls, fractures, disability, and death. Recent reviews have catalogued extracellular vesicle (EV)-associated microRNAs in muscle-bone crosstalk, but intracellular microRNA function, EV association, experimentally administered EVs, and physiological tissue-to-tissue transfer are often discussed together. This focused narrative review applies an author-defined, non-validated four-tier framework to separate these inference levels using prespecified criteria for tissue-of-origin tracing, EV characterization, cargo perturbation, recipient validation, and in vivo phenotype. Within the studies reviewed, miR-125a-5p is the most complete preclinical muscle-to-bone candidate pathway, but its Tier-A assignment is provisional and supports causality only in the reported mouse models; it does not establish an exclusive single-cargo mechanism or human physiological transfer. Other muscle-cell EV microRNAs provide mechanistic but less complete evidence. No equivalent physiological bone-to-muscle EV-microRNA pathway meets Tier A; bone marrow stromal cell-derived EV miR-486-5p represents an experimentally administered therapeutic product rather than endogenous bone-to-muscle signaling. Most included studies concern related muscle or bone conditions or mechanistic models rather than directly defined osteosarcopenia. Human studies are small and heterogeneous, and none combines rigorous tissue-of-origin assignment, a prespecified osteosarcopenia phenotype, paired bone and muscle outcomes, and external validation. EV biomarkers and RNA/EV therapies therefore remain investigational. This evidence-based asymmetry, rather than another catalogue of candidate microRNAs, distinguishes the present review and defines priorities for tissue-specific tracing, cargo-specific rescue, independent human validation, and prospective tests of clinical utility.