LDL receptor affects the skeletal muscle and bone microstructure of female mouse through the Wnt/β-catenin signaling pathway.

OBJECTIVE

Osteosarcopenia, a composite disorder of age-related sarcopenia and osteoporosis, currently lacks targeted therapeutic interventions. We hypothesized that skeletal muscle-specific LDLR knockdown could reverse musculoskeletal functional decline via the Wnt/β-catenin signaling pathway.

METHODS

19-month-old female C57BL/6J mice were divided into elderly control (E-Con), elderly AAV vector-only (E-KD-C), and elderly LDLR knockdown (E-KD) groups, with an additional 3-month-old young control (Y-Con) group. Each group n = 6. After 8 weeks, the following parameters were assessed: grip strength, muscle histology (H&E staining, Goldner staining), bone microarchitecture (micro-CT scanning), and Wnt pathway components (RT-qPCR/Western blot).

RESULTS

Compared to Y-Con, Aged mice exhibited severe muscle atrophy (grip strength decline) and trabecular bone loss. LDLR knockdown in E-KD mice significantly enhanced grip strength and upregulated MYF5 and MYH2 expression. Furthermore, this intervention improved trabecular parameters (including bone volume BV, bone surface BS, and trabecular thickness Tb.Th) and activated the β-catenin signaling pathway through post-transcriptional regulation of FZD7 and LRP5.

CONCLUSION

Skeletal muscle LDLR knockdown improves sarcopenia by reactivating the Wnt/β-catenin signaling pathway, providing a potential therapeutic target for musculoskeletal aging.