Fenofibrate Attenuates Rotator Cuff Muscle Fatty Infiltration via Modulation of the PPARα-FABP4 Pathway.

BACKGROUND

Fatty infiltration of the rotator cuff muscle is a critical prognostic factor associated with poor tendon healing and high retear rates after rotator cuff tear (RCT). Recent studies have identified fatty acid binding protein 4 (FABP4) as a hypoxia- and inflammation-responsive lipid chaperone that may drive adipogenic degeneration in injured muscle tissue.

PURPOSE: To evaluate whether fenofibrate-a peroxisome proliferator-activated receptor alpha (PPARα) agonist approved for the treatment of hyperlipidemia-could prevent fatty infiltration by modulating FABP4 expression in vitro and in a RCT repair rat model.

STUDY

DESIGN

Controlled laboratory study.

METHODS

The expression of FABP4 under hypoxic conditions was evaluated in C2C12 myoblasts treated with fenofibrate (10 and 100 μm) using quantitative real-time polymerase chain reaction (qRT-PCR). To investigate molecular mechanisms, the expression levels of upstream regulators and adipocyte differentiation-related genes were also measured by qRT-PCR after fenofibrate treatment in the same cell line. For the in vivo study, an RCT model was established by transection of the right supraspinatus tendon. Fenofibrate (20 mg/kg) was locally administered 3 times over 2 days after surgery. At 6 weeks, the supraspinatus muscle was harvested. Fatty infiltration was qualitatively and quantitatively assessed using histological analysis, and the expression of relevant metabolic and adipogenic genes was analyzed by qRT-PCR.

RESULTS

In vitro, fenofibrate significantly downregulated FABP4 expression in a dose-dependent manner under hypoxic conditions (fenofibrate, 10 µm: 0.86 ± 0.12 [P < .01]; 100 µm: 0.32 ± 0.06 [P < .01]; control: 1.12 ± 0.17). Expression of PPARα (fenofibrate, 10 µm: 2.46 ± 0.10 [P < .01]; 100 µm: 2.75 ± 0.13 [P < .01]; control: 1 ± 0.10), an upstream regulator of FABP4, was significantly upregulated after treatment in a similarly dose-dependent fashion. In vivo, fenofibrate-treated shoulders demonstrated marked suppression of fatty infiltration, as confirmed by both qualitative histological evaluation and quantitative fat area analysis (fenofibrate: 6.66% ± 10.38%; control: 46.38% ± 21.79% [P < .01]). Gene expression profiling revealed that PPARα was significantly upregulated (fenofibrate: 10.65 ± 7.02; control: 1 ± 0.62 [P < 005]), while FABP4 expression was significantly reduced (fenofibrate: 2.64 ± 0.91; control: 5.44 ± 2 [P < .05]) in the fenofibrate group compared with controls.

CONCLUSION

Fenofibrate reduces muscle fatty infiltration by modulating the PPARα-FABP4 metabolic pathway in the setting of RCT. These findings support the potential of fenofibrate as a drug repositioning candidate to prevent muscle degeneration and enhance tissue quality in rotator cuff (RC) injuries.

CLINICAL RELEVANCE: Fenofibrate, with its established clinical safety profile, may represent a novel pharmacologic strategy to improve outcomes after RC repair by targeting fatty infiltration.