Myokine Signaling in Sarcopenia-Associated Chronic Musculoskeletal Pain: A Systematic Review of Inflammatory Mechanisms

Chronic musculoskeletal pain and sarcopenia co-occur at rates exceeding epidemiological independence in older adults. However, no systematic review has examined whether exercise-induced myokine signaling suppresses shared NF-κB–driven inflammatory pathways to concurrently address chronic pain and sarcopenic muscle loss in older adults. Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, Scopus, and Embase (January 2000–March 2026) and included 32 studies (RCTs, cohort, cross-sectional, and mechanistic designs) in adults aged ≥45 years with chronic musculoskeletal pain and/or sarcopenia; studies lacking an exercise component or human mechanistic relevance were excluded, and findings were qualitatively synthesized. The included studies suggest that persistent NF-κB hyperactivation—driven by SASP, LPS–TLR4 signaling, and mitochondrial ROS—is associated with both sarcopenic muscle loss and pain sensitization. Evidence from included studies indicates that contracting skeletal muscle secretes IL-6, IL-15, irisin, BDNF, and myostatin, which were frequently associated with suppression of NF-κB activity, attenuation of NLRP3 inflammasome activation, and improvement in pain inhibition—suggesting a hypothesized shared mechanistic pathway that awaits direct validation in trials enrolling older adults with co-confirmed sarcopenia and chronic pain. Multicomponent training emerged as the modality most consistently associated with concurrent benefits for both conditions across included studies. The synthesized evidence supports considering a two-phase approach—pain neuroscience education followed by progressive resistance training—as a hypothesis-driven framework to improve exercise adherence and myokine responses. These findings suggest that myokine signaling represents a plausible shared mechanistic pathway linking exercise to concurrent improvements in sarcopenia and chronic pain, warranting direct validation in future trials.