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-β (TGF-β) 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-β 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-β 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-β 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-β gene and protein expression at both 2 and 6 weeks after RCT. Evaluation of the TGF-β signaling pathway revealed an increase in SMAD2 activation but not in SMAD3. There was an increase in profibrotic markers collagen I, collagen III, and α-smooth muscle actin. Conclusions TGF-β signaling is significantly upregulated in rat supraspinatus muscles after RCTs.

Rotator cuff tears (RCTs) are among the most common musculoskeletal injuries seen by orthopaedic surgeons. Clinically, massive cuff tears lead to unique pathophysiological changes in rotator cuff muscle, including atrophy, and massive fatty infiltration, which are rarely seen in other skeletal muscles. Studies in a rodent model for RCT have demonstrated that these histologic findings are accompanied by activation of the Akt/mammalian target of rapamycin (mTOR) and transforming growth factor-b (TGF-b) pathways following combined tendon-nerve injury. The purpose of this study was to compare the histologic and molecular features of rotator cuff muscle and gastrocnemius muscle-a major hindlimb muscle, following combined tendon-nerve injury. Six weeks after injury, the rat gastrocnemius did not exhibit notable fatty infiltration compared to the rotator cuff. Likewise, the adipogenic markers SREBP-1 and PPARg as well as the TGF-b canonical pathway were upregulated in the rotator cuff, but not the gastrocnemius. Our study suggests that the rat rotator cuff and hindlimb muscles differ significantly in their response to a combined tendon-nerve injury. Clinically, these findings highlight the unique response of the rotator cuff to injury, and may begin to explain the poor outcomes of massive RCTs compared to other muscle-tendon injuries. ß

Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model tration, and fibrosis related genes. Significantly increased adipocytes, muscle fatty infiltration, and collagen deposition was observed in rotator cuff muscles in the tendon repair group compared to the control group. Conclusions: rotator cuff muscle undergoes degradation changes including fatty infiltration and fibrosis even after the tendons are repair immediately after rupture. Level of Evidence: Basic Science Study. IntroductionRotator cuff tears (RCTs) are the most common shoulder injury seen by orthopedic surgeons and are especially frequent among the aging patient population. The prevalence of full thickness RCTs is estimated between 15 and 51%, with higher rates in the elderly population 1 . Although repair of small tears is successful in alleviating pain and improving shoulder biomechanics, successful repair of larger RCTs still remains a challenge 2,3 . As the incidence of rotator cuff injuries continues to rise with an aging patient population, management and knowledge of the etiopathogenesis of RCTs 4 is a topic of concern. Several muscle-based factors have been identified to affect the outcome of rotator cuff repairs. It has been demonstrated that the degree of atrophy correlates with the size of the tear and, more importantly, with clinical outcomes 5,6 . Similarly, fatty infiltration has been shown to also correlate with poor outcomes following rotator cuff repair 6,7 . Although the clinical effects of muscle fibrosis on rotator cuff injuries are not well quantified, muscle fibrosis is an important contributor to muscle stiffness and is seen in many other muscle injury models 8 . Thus, these three physiological traits, muscle atrophy, fatty infiltration, and muscle fibrosis, are likely key factors governing outcome after rotator cuff injury and repair. Animal models are useful tools to study the molecular mechanisms of muscle atrophy, fatty infiltration, and fibrosis that are observed in the setting of rotator cuff tears in patients. While there are multiple RCTs studies conducted in rat or mouse models 9-12 , the sheep model, as a larger animal model, may more closely mirror the pathophysiologic changes observed in human RCTs 13 since the infraspinatus tendons of sheep SummaryIntroduction: rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Muscle atrophy and fatty infiltration of the muscle are crucial factors that dictate the outcome following rotator cuff surgery. Though less studied in humans, rotator cuff muscle fibrosis has been seen in animal models as well and may influence outcomes as well. The purpose of this study was to determine if the rotator cuff would develop muscle changes even in the setting of an acute repair in a sheep model. We hypothesized that fatty infiltration and fibrosis would be present even after an acute repair six months after initial surgery. Methods: twelve female adult sheep underwent an acute rotator cuff tear and immediate repair on ...

Conclusion: this result suggests that BMP signaling inhibits RC muscle atrophy but promotes fatty infiltration.

Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model tration, and fibrosis related genes. Significantly increased adipocytes, muscle fatty infiltration, and collagen deposition was observed in rotator cuff muscles in the tendon repair group compared to the control group. Conclusions: rotator cuff muscle undergoes degradation changes including fatty infiltration and fibrosis even after the tendons are repair immediately after rupture. Level of Evidence: Basic Science Study.

Introduction: Rotator cuff (RC) tears are common tendon injuries. Clinically, both muscle atrophy and fatty infiltration have generally been attributed to poor functional outcomes. Matrix metalloproteinase-13 plays a crucial role in extracellular matrix remodeling in many physiological and pathological processes. Nevertheless, its role in rotator cuff muscle atrophy and fatty infiltration remains unknown. The purpose of this study is to define the functional role of MMP-13 in rotator cuff muscle atrophy and fatty infiltration using a mouse RC tears model. Materials and methods: Unilateral complete supraspinatus and infraspinatus tendon transection and suprascapular nerve transection was performed on nine of MMP-13 (-/-) knockout and nine of MMP-13 (+/+) wildtype mice at 3 months old. Mice were sacrificed 6 weeks after surgery. Supraspinatus (SS) and infraspinatus (IS) muscles were harvested for histology and gene expression analysis with RT-PCR. Results: Six weeks after RC surgery, no significant difference in muscle atrophy and fibrosis between MMP-13 knockout and wild type mice was observed. However, there was a significant increase in the amount of fatty infiltration in MMP-13 knockout mice compared to the wild types. Muscles from MMP-13 knockout mice have significantly higher expression of fatty infiltration related genes. Discussion: Results from this study suggest that MMP-13 plays a crucial role in rotator cuff muscle fatty degeneration. This novel finding suggests a new molecular mechanism that governs RC muscle FI and MMP-13 may serve as a target for therapeutics to treat muscle FI after RC tears.

SummaryIntroduction: Rotator cuff (RC) tears are common tendon injuries. Clinically, both muscle atrophy and fatty infiltration have generally been attributed to poor functional outcomes. Matrix metalloproteinase-13 plays a crucial role in extracellular matrix remodeling in many physiological and pathological processes. Nevertheless, its role in rotator cuff muscle atrophy and fatty infiltration remains unknown. The purpose of this study is to define the functional role of MMP-13 in rotator cuff muscle atrophy and fatty infiltration using a mouse RC tears model. Materials and methods: Unilateral complete supraspinatus and infraspinatus tendon transection and suprascapular nerve transection was performed on nine of MMP-13 (-/-) knockout and nine of MMP-13 (+/+) wildtype mice at 3 months old. Mice were sacrificed 6 weeks after surgery. Supraspinatus (SS) and infraspinatus (IS) muscles were harvested for histology and gene expression analysis with RT-PCR. Results: Six weeks after RC surgery, no significant difference in muscle atrophy and fibrosis between MMP-13 knockout and wild type mice was observed. However, there was a significant increase in the amount of fatty infiltration in MMP-13 knockout mice compared to the wild types. Muscles from MMP-13 knockout mice have significantly higher expression of fatty infiltration related genes.

Conclusion: this result suggests that BMP signaling inhibits RC muscle atrophy but promotes fatty infiltration.