Inhibiting MicroRNA-141-3p Improves Musculoskeletal Health in Aged Mice

Emerging evidence shows that the microRNA-141-3p is involved in various age-related pathologies. Previously, our group and others reported elevated levels of miR-141-3p in several tissues and organs with age. Here, we inhibited the expression of miR-141-3p using antagomir (Anti-miR-141-3p) in aged mice and explored its role in healthy aging. We analyzed serum (cytokine profiling), spleen (immune profiling), and overall musculoskeletal phenotype. We found decreased levels of pro-inflammatory cytokines (such as TNF-a, IL-10, IFN-y) in serum with Anti-miR-141-3p treatment. The flow-cytometry analysis on splenocytes revealed decreased M1 (pro-inflammatory) and increased M2 (anti-inflammatory) populations. We also found improved bone microstructure and muscle fiber size with Anti-miR-141-3p treatment. Molecular analysis revealed that miR141-3p regulates the expression of AU-rich RNA-binding factor 1 (AUF1) and promotes senescence (p21, p16) and pro-inflammatory (TNF-a, IL-10, IFN-y) environment whereas inhibiting miR-141-3p prevents these effects. Furthermore, we demonstrated that the expression of FOXO-1 transcription factor was reduced with Anti-miR141-3p and elevated with silencing of AUF1 (siRNA-AUF1), suggesting crosstalk between miR-141-3p and FOXO-1. Overall, our proof-of-concept study demonstrates that inhibiting miR-141-3p could be a potential strategy to improve immune, bone, and muscle health with age.

Automated summary

Emerging evidence suggests that microRNA-141-3p plays a role in age-related pathologies. In this study, we inhibited miR-141-3p expression in aged mice and observed improved immune, bone, and muscle health. Treatment with Anti-miR-141-3p resulted in decreased pro-inflammatory cytokines, a shift from pro-inflammatory to anti-inflammatory immune cell populations, and improved bone microstructure and muscle fiber size. Molecular analysis revealed the role of miR-141-3p in regulating senescence and inflammation, as well as its potential crosstalk with FOXO-1 transcription factor. These findings suggest that inhibiting miR-141-3p may be a potential strategy for promoting healthy aging.