Aged Small Intestine Derived Small Extracellular Vesicles miR ‐214‐3p Leads to Intermuscular Fatty Infiltration Through Wnt/β‐Catenin Mediated Fibro‐Adipogenic Progenitors Adipogenesis

Age-related fat infiltration of skeletal muscle contributes to sarcopenia, declines in physical performance, and metabolic disorders such as insulin resistance in the elderly. However, the underlying mechanisms remain incompletely defined. Here, we investigated the effects of small extracellular vesicles (sEVs) derived from aged small-intestinal on intermuscular adipose tissue (IMAT) infiltration. In mouse models, systemic tail-vein administration of these sEVs in vivo, together with direct exposure of cultured cells to sEVs in vitro, promoted adipogenic differentiation of fibro-adipogenic progenitors (FAPs), thereby increasing IMAT infiltration and decreasing muscle strength in young recipient mice. High-throughput sequencing and functional analyses identified sEVs-derived miR-214-3p as a critical mediator of this phenotype; this microRNA suppresses the Wnt/β-catenin pathway by directly targeting the gene encoding β-catenin. Collectively, these findings reveal a mechanistic connection between intestinal signaling and muscle composition during aging, highlighting the gut-muscle axis as a promising therapeutic target for prevention or treatment of sarcopenia.