Rotator cuff disease is one of the most common shoulder problems in adults. In the U.S. alone, up to 40% of individuals sixty years of age and older are affected, with approximately 75,000 rotator cuff repairs performed annually. Despite advances in treatments, failure of rotator cuff repairs continues to pose a major problem. Furthermore, little is known about the basic mechanisms that play a role in rotator cuff healing, including tendon degeneration and repair, tendon-to-bone healing, the role of inflammation and bursitis in repair, and the role of muscle response to injury.
One of the potential causes of failed rotator cuff repair is inability of the rotator cuff muscles to respond to injury and promote repair. In prior studies, authors have shown that the rotator cuff muscles are replaced by fat in the presence of a massive rotator cuff tear, chronic rotator cuff disease, and muscle denervation from neurologic injury1-5. Some earlier molecular studies have also shown that gene expression is altered in response to rotator cuff injury and that alterations are associated with muscle atrophy and fatty infiltration6-8.
In their present paper, Choo et al. investigated the changes in gene expression that occur in skeletal muscle in association with rotator cuff pathology (bursitis, tendinopathy, and full-thickness and massive rotator cuff tears). The expression levels of five myogenic, six adipogenic, and nine fibrogenic genes were analyzed in the supraspinatus muscle of patients with each of these classes of pathology. The authors hypothesized that genes are differentially expressed in patients with various rotator cuff tendon tear severities. The results demonstrated increased expression of the myogenic genes in patients with bursitis, increased expression of the fibrotic and adipogenic genes in patients with a full-thickness tear, and downregulated expression of the fibrotic, adipogenic, and myogenic genes in patients with a massive rotator cuff tear.
Although these results suggest that the expression levels of these families of genes in skeletal muscle are associated with the severity of rotator cuff pathology, the study has some deficiencies that are important to note. The authors acknowledge that the expression of the housekeeping gene GAPDH (the gene for the enzyme glyceraldehyde 3-phosphate dehydrogenase, against which gene expression levels are commonly normalized in such studies) was highly variable across samples, and the gene for 18S ribosomal RNA was used as a reference instead. However, it is possible that some of the reported variations in expression of the adipogenic, myogenic, or fibrotic genes may reflect variations in overall gene expression rather than in expression of these specific genes. To respond to these concerns, the authors do provide absolute expression values for the readers. It is also concerning that only two of the samples were from patients with a massive rotator cuff tear and that there was no control group against which all of the groups could be compared. Additionally, without use of a localization method such as in situ hybridization or immunohistochemistry, it is not possible to be certain that the measured expression was due to skeletal muscle cells alone, and further studies should be performed to localize gene expression.
Another concern involves the imaging results in the study. After reviewing the MRI (magnetic resonance imaging) results and quantifying muscle and fat volumes in the suprascapular fossa, the authors state that “all of our patients fell into the Goutallier stage-I and II categories.” Therefore, despite the variability in tendon tear size, there were no significant associations between gene expression and MRI-based measures of fatty infiltration. It is concerning that substantial adipogenesis was not present according to MRI in those patients in whom expression of adipogenic genes was elevated. It is possible that the changes in gene expression had not yet had time to result in effects appreciable on MRI scans.
Despite these concerns, this study represents an important investigation into the basic molecular mechanisms involved in the pathophysiology of rotator cuff disease. There are many possible contributors to failed healing resulting in rotator cuff pathology, and the molecular changes that occur in the rotator cuff muscles are an important component9. The authors state that “an understanding of these gene expression patterns and complex muscular adaptations to a tear may lead to the development of new human therapeutics that may alter current treatment.” I agree that molecular therapeutics and targeted gene therapies are the new frontier in treatment of rotator cuff disease, and basic investigations such as these are critical to the development of these new treatment strategies.
1. Gerber C, Meyer DC, Schneeberger AG, Hoppeler H, von Rechenberg B. Effect of tendon release and delayed repair on the structure of the muscles of the rotator cuff: an experimental study in sheep. J Bone Joint Surg Am. 2004 Sep;86(9):1973-82.
2. Gerber C, Meyer DC, Frey E, von Rechenberg B, Hoppeler H, Frigg R, Jost B, Zumstein MA. Neer Award 2007: reversion of structural muscle changes caused by chronic rotator cuff tears using continuous musculotendinous traction. An experimental study in sheep. J Shoulder Elbow Surg. 2009 Mar-Apr;18(2):163-71. Epub 2008 Dec 18.
3. Laron D, Samagh SP, Liu X, Kim HT, Feeley BT. Muscle degeneration in rotator cuff tears. J Shoulder Elbow Surg. 2012 Feb;21(2):164-74.
4. Kim HM, Galatz LM, Lim C, Havlioglu N, Thomopoulos S. The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model. J Shoulder Elbow Surg. 2012 Jul;21(7):847-58. Epub 2011 Aug 10.
5. Shi LL, Boykin RE, Lin A, Warner JJ. Association of suprascapular neuropathy with rotator cuff tendon tears and fatty degeneration. J Shoulder Elbow Surg. 2014 Mar;23(3):339-46. Epub 2013 Sep 20.
6. Schmutz S, Fuchs T, Regenfelder F, Steinmann P, Zumstein M, Fuchs B. Expression of atrophy mRNA relates to tendon tear size in supraspinatus muscle. Clin Orthop Relat Res. 2009 Feb;467(2):457-64. Epub 2008 Oct 22.
7. Joshi SK, Liu X, Samagh SP, Lovett DH, Bodine SC, Kim HT, Feeley BT. mTOR regulates fatty infiltration through SREBP-1 and PPARγ after a combined massive rotator cuff tear and suprascapular nerve injury in rats. J Orthop Res. 2013 May;31(5):724-30. Epub 2012 Dec 13.
8. Killian ML, Lim CT, Thomopoulos S, Charlton N, Kim HM, Galatz LM. The effect of unloading on gene expression of healthy and injured rotator cuffs. J Orthop Res. 2013 Aug;31(8):1240-8. Epub 2013 Mar 18.
9. Isaac C, Gharaibeh B, Witt M, Wright VJ, Huard J. Biologic approaches to enhance rotator cuff healing after injury. J Shoulder Elbow Surg. 2012 Feb;21(2):181-90.