Myokines in exercise‑mediated bone homeostasis: Molecular signaling mechanisms and therapeutic implications for bone...

Skeletal muscle functions as an endocrine organ, secreting myokines that mediate interorgan communication with bone. Exercise‑induced myokines regulate bone homeostasis by orchestrating osteoblast differentiation, osteoclastogenesis, and osteocyte mechano‑sensing through key signaling pathways, including the Wnt/β‑catenin, mitogen‑activated protein kinase, phosphatidylinositol‑3‑kinase/AKT, nuclear factor kappa B and transforming growth factor‑beta/bone morphogenetic protein pathways. The present review provides a critical synthesis of the current evidence and proposes a conceptual framework for the tripartite muscle‑bone‑immune axis, which has not been systematically integrated into previous reviews. Emerging evidence highlights a tripartite muscle‑bone immune axis, wherein myokines modulate immune cells within the bone niche, with dysregulation contributing to age‑related osteoporosis and sarcopenia. Methodological innovations such as multi‑omics, single cell and spatial transcriptomics, organ‑on‑a‑chip platforms, and artificial intelligence are accelerating discovery. The present review synthesizes current knowledge on myokine mediated muscle‑bone crosstalk and evaluates the therapeutic implications for bone disorders.