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

Abstract

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.