MST1 inhibition mitigates fat deposition in rotator cuff tears by modulating the WNT/β-catenin pathway

Fatty infiltration of the supraspinatus muscle following rotator cuff tear (RCT) is a major pathological factor leading to poor functional outcomes, yet effective treatments are lacking. The kinase mammalian Sterile 20-like kinase 1 (MST1) has been implicated in metabolic disorders, but its role in RCT-associated muscle steatosis remains unexplored.

Using a murine RCT model, fatty infiltration was assessed via Oil Red O staining, triglyceride content, and expression of adipogenic markers. Fibro/adipogenic progenitors (FAPs) were isolated for in vitro mechanistic studies of MST1 on fatty infiltration. In vivo knockdown of MST1 was achieved via local lentiviral shRNA injection. Masson's trichrome staining and myogenic regulatory protein were used to evaluate muscle atrophy.

MST1 expression was upregulated in the supraspinatus muscle post-RCT, correlating with progressive lipid accumulation. MST1 knockdown in FAPs impaired adipogenic differentiation, reducing lipid droplets and the expression of PPARγ and FABP4. Mechanistically, MST1 depletion activated the WNT/β-catenin signaling pathway, and its inhibition reversed the anti-adipogenic effect. In vivo, MST1 knockdown attenuated fatty infiltration, suppressed the adipogenic program, and alleviated muscle atrophy in RCT mice.

Our findings unveil a pivotal role for MST1 in driving fatty infiltration by regulating FAP adipogenesis via the WNT/β-catenin pathway. Targeted inhibition of MST1 represents a promising therapeutic strategy to mitigate muscle steatosis and alleviate muscle atrophy after RCT.