Modulation of Wnt/β-Catenin Signaling by STAT3 Inhibition Restores Myogenic Capacity in Sarcopenia.

Background: Sarcopenia is a progressive disorder characterized by loss of skeletal muscle mass, strength, and function. Although STAT3 is known to regulate myogenic differentiation, its role in sarcopenia remains unclear.

Methods: STAT3 expression was assessed in skeletal muscle samples from sarcopenia patients and nonsarcopenic controls, as well as aged SAMP8 mice. C2C12 myoblasts were used to investigate the effects of STAT3 on proliferation and myogenic differentiation using gain- and loss-of-function approaches. The role of the Wnt/β-catenin pathway was examined using pathway-specific assays. In vivo, siRNA-mediated STAT3 knockdown was performed in aged SAMP8 mice to evaluate effects on muscle phenotype and endurance.

Results: STAT3 expression was significantly upregulated in muscle tissues from sarcopenia patients and aged mice, correlating with increased expression of the atrophy marker MuRF-1. STAT3 levels also rose during C2C12 cell differentiation. STAT3 overexpression suppressed C2C12 proliferation and myogenic differentiation, whereas knockdown enhanced both processes. Mechanistically, STAT3 inhibited Wnt/β-catenin signaling, reducing the expression of myogenic markers. In vivo, STAT3 silencing in aged mice increased muscle mass, improved treadmill performance, and decreased muscle atrophy markers.

Conclusion: STAT3 impairs myogenic proliferation and differentiation by negatively regulating the Wnt/β-catenin pathway, contributing to sarcopenia progression. Targeting STAT3 may serve as a promising therapeutic strategy for restoring muscle regeneration and function in sarcopenia.