Exosomal miRNAs in muscle-bone crosstalk: Mechanistic links, exercise modulation and implications for sarcopenia, osteoporosis and osteosarcopenia

This review investigates the emerging role of exosomal microRNAs (miRNAs) as pivotal mediators of bidirectional communication between the skeletal muscle and bone tissue, with significant implications for age-related musculoskeletal disorders. In aging populations, sarcopenia often coexists with osteoporosis, forming osteosarcopenia, which markedly increases fracture risk, disability, and mortality. While traditional paradigms emphasize mechanical loading and endocrine pathways, emerging evidence has revealed that exosomes carrying bioactive miRNAs represent a novel class of paracrine factors in the muscle-bone axis. We examined how muscle-derived exosomal miRNAs (miR-34a and miR-27a-3p) influence bone metabolism, while bone-derived exosomal miRNAs (miR-486-5p) modulate muscle physiology. For each miRNA, we identified the target messenger RNAs (mRNAs) and signaling mechanisms. Importantly, exercise has emerged as a potent modulator of this crosstalk, altering exosomal miRNA profiles to promote anabolic outcomes in both tissues. This bidirectional communication contributes to osteosarcopenia pathophysiology, leading us to propose a novel "Exosomal miRNA Regulatory Network" for diagnosis and pathogenesis. Exosomal miRNAs show promise as early biomarkers for subclinical deterioration and therapeutic targets. However, methodological challenges in exosome isolation, incomplete characterization of miRNA networks, and aging complexity must be addressed before clinical implementation.