Rotator cuff tears (RCTs) are among the most common upper extremity injuries seen by orthopaedic surgeons and primary care physicians, and the incidence of rotator cuff surgery continues to rise. As a result, the management of RCTs is a topic of concern, leading to the release of clinical practice guidelines (CPG), appropriate use criteria (AUC), and even a study on the social and economic value of rotator cuff repair.
As the rotator cuff ages, it becomes susceptible to degenerative tears. This can lead to shoulder dysfunction, including pain and the inability to raise the arm, which is the most common symptom prompting patients to seek care. Up to 20 percent of patients older than age 50 have evidence of symptomatic RCTs, and 49 percent of patients older than age 70 have asymptomatic RCTs.
RCTs are among the musculoskeletal injuries that orthopaedic surgeons treat initially with nonsurgical management. Although some patients remain asymptomatic, the natural history of RCTs is progression with an increase in symptoms and tear size over time.
A study published in 2009 reported on results after 6 months of nonsurgical treatment in 59 shoulders (54 patients; average age, 59 years). In the subgroup of patients who had symptomatic full-thickness RCTs, tear size increased more than 5 mm in 24 percent of patients; in 27 percent of patients, tear size increased from 2 mm to 5 mm, and remained unchanged in 36 percent of patients.
Despite the development of improved biomechanical constructs and arthroscopic techniques, clinical success rates in treating RCTs have remained relatively constant. Although treatment for small and medium-sized tears is relatively successful, large and massive tears remain a considerable challenge to the treating orthopaedic surgeon.
Muscle atrophy and fatty infiltration
Many factors contribute to the success of a rotator cuff repair, including tendon and bone quality, biomechanical strength of the repair construct, and patient compliance. In addition, muscle quality appears to have a major role in determining clinical outcomes.
Massive RCTs have been found to be associated with atrophy, fibrosis, and fatty infiltration (FI) of the supraspinatus and infraspinatus muscles (Fig. 1). Clinically, muscle atrophy and FI have been shown to be irreversible and have been correlated with poor functional outcomes following RCT repair.
The molecular mechanisms that lead to the development of rotator cuff muscle atrophy and FI have not been well-defined. Two key components in the development of these muscle changes appear to be unloading of the muscle-tendon unit and denervation of the muscle.
Akt-mTOR and muscle atrophy
The Akt-mTOR (mammalian target of rapamycin) pathway plays a central role in the signal transduction pathway that regulates muscle size. mTOR serves as a downstream effector in the IGF (insulin-like growth factor) pathway, insulin pathway, and mechanical pathways and regulates muscle protein synthesis. It is also involved in protein degradation by interfering with major muscle protein degradation pathways, including the autophagy and ubiquitin-proteasome pathway.
Recent studies of massive RCTs in a small animal model are investigating the role of the Akt-mTOR pathway in the development of muscle atrophy and FI. Data from these studies suggest that tendon transection and denervation affect the regulation of the Akt/mTOR pathway in fundamentally different ways.
After an isolated tendon injury, a small increase in muscle atrophy was seen, with downregulation of the Akt/mTOR pathway. Conversely, after denervation, muscle atrophy is significant, and Akt/mTOR activity, expression of atrophy-related genes (MuRF1 and MAFBx), and protein degradation increase. Thus, the Akt/mTOR pathway appears to have a central role in the development of muscle atrophy.
FI, Akt/mTOR, and PPARγ
Previous studies had suggested that the presence of adipocytes in atrophied rotator cuff muscles is due to the differentiation of pre-adipocytes into adipocytes. This process is mediated by the PPARγ (peroxisome proliferator activated receptor gamma) transcription factor.
PPARγ is the dominant regulator of adipogenesis and has been proven to be both necessary and sufficient for fat cell differentiation. A recent study on RCTs using a sheep model found that PPARγ expression increased following transection of the rotator cuff with significant FI development.
Interestingly, a small animal rotator cuff model has shown that PPARγ can be regulated by the Akt/mTOR pathway. An in vitro study has demonstrated that adipogenic differentiation induced by PPARγ up-regulation was under the control of transcription factor sterol regulatory element binding protein 1 (SREBP-1). The Akt/mTOR signaling pathway has been shown to regulate SREBP-1 activation, suggesting SREBP-1 is a link between Akt/mTOR activation and FI.
A recent small animal study evaluated the expression of Akt/mTOR, SREBP-1, and PPARγ in a rotator cuff model with a combined tendon and nerve injury. Increased mTOR activity and increased SREBP-1 and PPARγ expression was seen. However, the most important aspect of this study was that inhibiting mTOR with rapamycin not only led to decreased mTOR activity and decreased SREBP-1 and PPARγ expression, but also to the elimination of FI. Thus, the identification of these pathways has led to potential targets for pharmacologic inhibition of FI.
The role of imaging
Magnetic resonance imaging (MRI) is the gold standard for detecting rotator cuff injury. Assessing the muscle changes after rotator cuff injury is important for helping to guide clinical decision making, especially when determining when to consider repair versus reconstruction of massive rotator cuff tears. Muscle atrophy is graded by the size of the muscle belly relative to the supraspinatus fossa, and FI is graded based on the modified Goutallier classification that is qualitative, not quantitative.
As MRI technology has improved, preclinical and clinical studies are beginning to demonstrate that the amount of fat can be quantified using high resolution imaging. A small animal model was used to compare the amount of fat seen with MRI to that quantified with histology and biochemical quantification. The results showed that MRI was able to accurately quantify the amount of fat present in the rotator cuff to the amount seen in histologic and biochemical quantification. Thus, quantification of the amount of FI appears possible.
Translating this to clinical science, recent studies using the IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation) MRI sequence have quantified the presence of fat deposition across multiple disease processes, most commonly in the quantification of fatty deposition in the liver. The IDEAL sequence has also been used to quantify fat content in comparison with the modified Goutallier classification in the rotator cuff muscles. Significant correlation was observed between the semi-quantitative modified Goutallier classification grades and the quantitative IDEAL fat fracture values. The study also showed that IDEAL can have better correlation with clinical examination of shoulder strength, pain, and range of motion.
In summary, RCTs are a prevalent clinical problem. Research is clarifying the molecular mechanisms that result in muscle atrophy and FI following chronic RCTs. Improved imaging techniques are better able to quantify the degree of FI, which has important implications on clinical outcomes. Over the next decade, strategies to improve muscle function by decreasing FI will help improve clinical outcomes following cuff repair, and new imaging strategies such as IDEAL will help follow outcomes after cuff repair.
Brian T. Feeley, MD, is a sports medicine and shoulder surgeon in the University of California, San Francisco (UCSF) Sports Medicine Center and C. Benjamin Ma, MD, is Chief of Sports Medicine at UCSF.
Disclosure: Dr. Feeley—No conflicts; Dr. Ma—Zimmer, Slack Incorporated; Knee; American Orthopaedic Society for Sports Medicine; Arthroscopy Association of North America; International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine.
- Massive rotator cuff tears are challenging to treat and are associated with muscle atrophy and fatty infiltration (FI).
- Understanding the molecular mechanisms that lead to the development of rotator cuff muscle atrophy and FI may lead to novel treatments.
- New imaging techniques such as the IDEAL MRI sequence can help quantify the degree of FI, and enable clinicians to better counsel patients about strategies to improve muscle function, and help predict clinical outcomes after rotator cuff repair.
Bench to Bedside
“Bench to Bedside” articles highlight new translational research and are prepared by the AAOS Research Development Committee (RDC). The RDC—under the auspices of the Council on Research and Quality—serves as the primary liaison to the National Institutes of Health on issues in musculoskeletal research and oversees research advocacy events, the clinician scientist development programs, and the Kappa Delta Research Awards.
- Clinical Practice Guidline on Optimizing the Management of Rotator Cuff Problems
- Appropriate Use Criteria on Optimizing the Management of Full-thickness Rotator Cuff Tears
- The Societal and Economic Value of Rotator Cuff Repair
- Yamaguchi K, Tetro AM, Blam O, Evanoff BA, Teefey SA, Middleton WD: Natural history of asymptomatic rotator cuff tears: A longitudinal analysis of asymptomatic tears detected sonographically. J Shoulder Elbow Surg 2001 May-Jun;10(3):199–203.
- Maman E, Harris C, White L, Tomlinson G, Shashank M, Boynton E: Outcome of nonoperative treatment of symptomatic rotator cuff tears monitored by magnetic resonance imaging. J Bone Joint Surg Am 2009 Aug;91(8):1898–1906.
- Gladstone JN, Bishop JY, Lo IK, Flatow EL: Fatty infiltration and atrophy of the rotator cuff do not improve after rotator cuff repair and correlate with poor functional outcome. Am J Sports Med 2007 May;35(5):719–728.
- Shen PH, Lien SB, Shen HC, Lee CH, Wu SS, Lin LC: Long-term functional outcomes after repair of rotator cuff tears correlated with atrophy of the supraspinatus muscles on magnetic resonance images. J Shoulder Elbow Surg 2008 Jan-Feb;17(1 Suppl):1S–7S.
- Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, et al: Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001 Nov;3(11):1014–1019.
- Liu X, Joshi SK, Samagh SP, Dang YX, Laron D, Lovett DH, et al: Evaluation of Akt/mTOR activity in muscle atrophy after rotator cuff tears in a rat model. J Orthop Res 2012 Sep;30(9):1440–1446.
- Frey E, Regenfelder F, Sussmann P, Zumstein M, Gerber C, Born W, et al: Adipogenic and myogenic gene expression in rotator cuff muscle of the sheep after tendon tear. J Orthop Res 2009 Apr;27(4):504–509.
- Itoigawa Y, Kishimoto KN, Sano H, Kaneko K, Itoi E: Molecular mechanism of fatty degeneration in rotator cuff muscle with tendon rupture. J Orthop Res 2011 Jun;29(6):861–866.
- 9Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, et al: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999 Oct;4(4):611–617.
- Fajas L, Schoonjans K, Gelman L, Kim JB, Najib J, Martin G, et al: Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: Implications for adipocyte differentiation and metabolism. Mol Cell Biol 1999 Aug;19(8):5495–5503.
- Krycer JR, Sharpe LJ, Luu W, Brown AJ: The Akt-SREBP nexus: Cell signaling meets lipid metabolism. Trends Endocrinol Metab 2010 May;21(5):268–276.
- Joshi SK, Liu X, Samagh SP, Lovett DH, Bodine SC, Kim HT, et al: mTOR regulates fatty infiltration through SREBP-1 and PPARy after a combined massive rotator cuff tear and suprascapular nerve injury in rats. J Orthop Res 2012, in press.
- Samagh SP, Kramer EJ, Melkus G, Laron D, Bodendorfer BM, Natsuhara K, et al: MRI quantification of fatty infiltration and muscle atrophy in a mouse model of rotator cuff tears. J Orthop Res 2013 Mar;31(3):421–426.
- Nardo L, Karampinos DC, Lansdown DA, Carballido-Gamio J, Ma CB, Link TM, Krug R: Quantitative Assessment of Fat Infiltration in the Rotator Cuff Muscles using MRI. JMRI 2013, accepted.