Directional Muscle-to-Bone Crosstalk via the Muscle Secretome: A Systematic Review

Skeletal muscle communicates biochemically with bone via a secretome consisting of soluble factors and extracellular vesicles (EVs). This secretory activity is regulated by mechanical stimuli and the muscle's metabolic state. The aim of this systematic review was to evaluate the effects of the muscle secretome, specifically muscle-derived conditioned media and EVs, on bone mesenchymal stem/stromal cells (MSCs), osteoblasts, osteoclasts, and bone-related outcomes in in vitro and in vivo models. Following PRISMA guidelines, PubMed and Web of Science were searched for original studies testing the muscle-derived secretome on MSCs, bone cells, or bone tissue, identifying 572 studies, of which 31 met the inclusion criteria. Risk of bias was assessed using SYRCLE for in vivo studies and a modified SYRCLE tool for in vitro studies. MISEV2023 terminology was applied. The majority of the included studies reported predominantly positive effects of secretome from healthy or mechanically stimulated muscle on MSC proliferation and osteogenic differentiation, improved osteoblast function, and suppressed osteoclast formation, with multiple in vivo confirmations. Conversely, secretome from atrophic/estrogen-deficient muscle inhibited osteogenesis and promoted osteoclastogenesis. Risk of bias and reporting limitations were common: heterogeneous dosing/reporting, incomplete reporting of purity, contaminants, and functional assay controls according to MISEV guidelines, and suboptimal SYRCLE domains in in vivo studies. The direction of muscle-to-bone biochemical crosstalk reflects muscle health-anabolic/antiresorptive when muscle is healthy or mechanically active, catabolic/proresorptive when muscle is atrophic or estrogen-deficient. These findings support exercise- and exerkine-based approaches, as well as EV-based therapeutics for osteoporosis or osteosarcopenia.