Exercise-mediated muscle-bone crosstalk in osteosarcopenia: potential integration through the LIF/LIFR/STAT3...

Osteosarcopenia, the coexistence of osteoporosis and sarcopenia, increases risks of falls, fractures, disability, and mortality in older adults. Exercise is widely recognized as the most effective non-pharmacological strategy to improve both muscle and bone health, yet the molecular mechanisms underlying coordinated musculoskeletal adaptation remain incompletely understood. Among exercise-responsive myokines, leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, has attracted increasing attention because it is rapidly induced by muscle contraction and mechanical loading. Upon binding to the LIF receptor (LIFR)/glycoprotein 130 (gp130) complex, LIF activates downstream Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling, which regulates satellite cell proliferation, muscle regeneration, osteoblast differentiation, and load-induced bone formation. Based on emerging evidence that is predominantly derived from indirect or context-specific studies, we propose that the LIF/LIFR/STAT3 signaling pathway may contribute to skeletal muscle homeostasis, bone remodeling, and mechanotransduction, and may potentially participate in muscle-bone crosstalk during exercise adaptation. In this review, we synthesize current evidence supporting this hypothesis, critically discuss its context-dependent effects, and highlight key knowledge gaps, particularly the lack of direct in vivo evidence in osteosarcopenia models. Overall, the LIF/LIFR/STAT3 signaling pathway may represent a biologically plausible candidate mechanism through which exercise may promote coordinated muscle-bone adaptation, although direct experimental validation, particularly in osteosarcopenia models, remains necessary before this pathway can be considered a therapeutic target.