Potential of IL-33 as a Novel Myokine in Sarcopenia-Osteoporosis Communication: Insights from Mendelian Randomization
Mingchong Liu, Jiaming Wang, Xiao Fu, Chensong Yang, Jinglei Zhao, Guixin SunIntroduction:
Inflammaging, a term describing the chronic, low-grade inflammatory state associated with aging, is implicated in various age-related diseases. Inflammatory proteins are central to inflammaging and bone-muscle communication. This study sought to investigate the role of inflammatory proteins as potential myokines and osteokines in the context of sarcopenia-osteoporosis crosstalk using a convenient and efficient method, Mendelian Randomization (MR).
Methods:
We employed a network-based MR approach, structuring analyses into forward and reverse directions. In forward analyses (inflammatory proteins as exposures), we examined their impact on sarcopenia traits and osteoporosis. Reverse analyses (inflammatory proteins as outcomes) assessed the influence of sarcopenia and osteoporosis on protein levels. Our analysis included 91 inflammatory proteins, three sarcopenia traits, and osteoporosis outcomes.
Results:
In forward analyses, we identified 24 significant causal relationships between inflammatory proteins and outcomes. Reverse analyses revealed 40 significant associations. Seven proteins emerged as key mediators of sarcopenia-osteoporosis interactions: IL-33, RANKL, CXCL1, CXCL5, CX3CL1, TNFB, and CD5. Notably, a causal link was found between poor handgrip strength and downregulated IL-33 (effect = -0.104), and downregulated IL-33 was causally associated with an increased risk of osteoporosis (effect = -0.003).
Discussion:
The identification of IL-33 as a potential novel myokine not only underscores the importance of inflammaging in musculoskeletal health but also highlights IL-33 as a promising therapeutic target for interventions targeting muscle-bone crosstalk in older adults. However, further experimental studies are warranted to validate the role of IL-33 in this context and to explore the underlying biological mechanisms.
Conclusion:
Our findings highlight IL-33 as a promising novel myokine involved in sarcopenia- osteoporosis communication. This MR analysis provides mechanistic insights into the inflammatory basis of these age-related conditions and suggests IL-33 as a potential therapeutic target for interventions aiming to improve muscle-bone health in older adults.