Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears

Background: Muscle atrophy, fatty infiltration, and fibrosis of the muscle have been described as important factors governing outcome after rotator cuff injury and repair. Muscle fibrosis is also thought to have a role in determining muscle compliance at the time of surgery. The transforming growth factor-beta (TGF-beta) pathways are highly conserved pathways that exert a potent level of control over muscle gene expression and are critical regulators of fibrosis in multiple organ systems. It has been shown that TGF-beta can regulate important pathways of muscle atrophy, including the Akt/mammalian target of rapamycin pathway. The purpose of this study was to evaluate the expression of TGF-beta and its downstream effectors of fibrosis after a massive rotator cuff tear (RCT) in a previously established rat model. Methods: To simulate a massive RCT, infraspinatus and supraspinatus tenotomy and suprascapular nerve transection were performed on Sprague-Dawley rats with use of a validated model. Two and 6 weeks after surgery, supraspinatus muscles were harvested to study alterations in TGF-beta signaling by Western blotting, quantitative polymerase chain reaction, and histologic analysis. Results: There was a significant increase in fibrosis in the rotator cuff muscle after RCT in our animal model. There was a concomitant increase in TGF-beta gene and protein expression at both 2 and 6 weeks after RCT. Evaluation of the TGF-beta signaling pathway revealed an increase in SMAD2 activation but not in SMAD3. There was an increase in profibrotic markers collagen I, collagen III, and alpha-smooth muscle actin. Conclusions: TGF-beta signaling is significantly upregulated in rat supraspinatus muscles after RCTs. (C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees.