Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: An animal model study

Fatty degeneration of the rotator cuff muscles is an irreversible change resulting from chronic rotator cuff tear and is associated with poor clinical outcomes following rotator cuff repair. We evaluated the effect of Tamoxifen, a competitive estrogen receptor inhibitor, on fatty degeneration using a mouse model for chronic rotator cuff tear. Sixteen adult mice were divided into two diet groups (Tamoxifen vs. Regular) and subjected to surgical creation of a large rotator cuff tear and suprascapular nerve transection in their left shoulder with the right shoulder serving as a control. The rotator cuff muscles were harvested at 16 weeks and subjected to histology and RT‐PCR for adipogenic and myogenic markers. Histology showed substantially decreased atrophy and endomysial inflammation in Tamoxifen group, but no significant differences in the amount of intramuscular adipocytes and lipid droplets compared to the Regular group. With RT‐PCR, the operated shoulders showed significant upregulation of myogenin and PPAR‐γ, and downregulation of myostatin compared to the nonsurgical shoulder. No significant differences of gene expression were found between the two diet groups. Our study demonstrated that tamoxifen diet leads to decreased muscle atrophy and inflammatory changes following chronic rotator cuff tear, but has no apparent effect on adipogenesis. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1846–1853, 2015.     

Costamere protein expression and tissue composition of rotator cuff muscle after tendon release in sheep

Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found the activity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained unchanged. At 2 weeks after tendon release, muscle volume decreased by 17 cm³ from an initial 185 cm³, the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm³, contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decrease of muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clinically, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. © 2017 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:272–281, 2018.     

Lateral to medial fibro‐adipogenic degeneration are greater in infraspinatus than supraspinatus following nerve and tendon injury of murine rotator cuff

Small animal models of massive tears of the rotator cuff (RC) were introduced a decade ago and have been extensively used to study the pathophysiology of chronically injured RC. Transection of rodent suprascapular nerve and RC tendon results in progressive muscle atrophy, fibrosis and fat accumulation and affect the infraspinatus and supraspinatus muscles similarly to that seen in the setting of massive RC tears in humans. The purpose of this study was to perform a comprehensive and detailed analysis of the kinetics of fibrotic scar and adipose tissue development comparing phenotypic differences between chronically injured infraspinatus and supraspinatus. Automatic mosaic imaging was used to create large image of whole infraspinatus or supraspinatus sectioned area for quantification of spatial heterogeneity of muscle damage. Pathologic changes advanced from the lateral site of transection to the medial region far from the transection site. A prominent, accelerated muscle fibrosis and fat accumulation was measured in injured infraspinatus compared to supraspinatus. Furthermore, adipose tissue occupied significantly larger area than that of fibrotic tissue in both muscles but was greater in infraspinatus within 6 weeks post induction of injury. Our findings confirm that infraspinatus is more susceptible to accelerated chronic degeneration and can be used to identify the physiological functions that distinguish between the response of infraspinatus and supraspinatus in the setting of massive tears. Whether these pathologic differences observed in mice are reflected in humans is one key aspect that awaits clarification.     

MRI quantification of fatty infiltration and muscle atrophy in a mouse model of rotator cuff tears

Rotator cuff pathology is the most common shoulder problem seen by orthopedic surgeons. Rotator cuff muscle fatty infiltration and muscle atrophy are common in larger tears and are considered predicting factors for the prognosis of cuff repair. Clinically, MRI is the gold standard in determining fatty infiltration and muscle atrophy; however, analysis for MRI imaging is primarily qualitative in nature with the results lacking further validation. We have recently developed a mouse model of rotator cuff tears. The goal of this study is to quantify and verify rotator cuff muscle atrophy and fatty infiltration using high‐resolution MRI in our mouse model. The rotator cuff muscles were analyzed for fat using a triglyceride quantification assay (TQA), muscle volume was measured through water displacement (WD), and histology. The study revealed that MRI had a high correlation with fat as measured with histology and TQA (R² = 098). MRI also correlated well with atrophy measured with WD and wet weight. This suggests that MRI is a reliable modality in evaluating the progression of fatty infiltration and muscle atrophy following rotator cuff tears in a small animal model. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 421–426, 2013     

Biceps tendon properties worsen initially but improve over time following rotator cuff tears in a rat model

Damage to the biceps tendon is often seen in conjunction with rotator cuff tears. However, controversy exists regarding its role in the shoulder and its optimal treatment. A previous study determined that biceps tendons were detrimentally affected in the presence of rotator cuff tears in the rat model and this damage worsened over time. However, whether this damage progresses at later time points to provide a chronic model is unknown. The objective of this study was to determine the changes in the biceps tendon in the presence of a cuff tear over time. Our hypothesis was that histological, compositional, organizational, and mechanical properties would worsen with time. We detached the supraspinatus and infraspinatus tendons of 48 rats and evaluated these properties at 1, 4, 8, and 16 weeks postdetachment. Properties worsened through 8 weeks, but improved between 8 and 16 weeks. We therefore conclude that biceps tendon changes in this model are not truly chronic. Additionally, it has been shown that infraspinatus properties in this model return to normal by 16 weeks, when biceps properties improve, indicating that earlier repair of one or more of the rotator cuff tendons may lead to resolved pathology of the long head of the biceps tendon. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:874–879     

Rotator cuff muscle degeneration and tear severity related to myogenic,adipogenic, and atrophy genes in human muscle

Large rotator cuff tear size and advanced muscle degeneration can affect reparability of tears and compromise tendon healing. Clinicians often rely on direct measures of rotator cuff tear size and muscle degeneration from magnetic resonance imaging (MRI) to determine whether the rotator cuff tear is repairable. The objective of this study was to identify the relationship between gene expression changes in rotator cuff muscle degeneration to standard data available to clinicians. Radiographic assessment of preoperative rotator cuff tear severity was completed for 25 patients with varying magnitudes of rotator cuff tears. Tear width and retraction were measured using MRI, and Goutallier grade, tangent (tan) sign, and Thomazeau grade were determined. Expression of myogenic‐, adipogenic‐, atrophy‐, and metabolism‐related genes in biopsied muscles were correlated with tear width, tear retraction, Goutallier grade, tan sign, and Thomazeau grade. Tear width positively correlated with Goutallier grade in both the supraspinatus (r = 0.73) and infraspinatus (r = 0.77), along with tan sign (r = 0.71) and Thomazeau grade (r = 0.68). Decreased myogenesis (Myf5), increased adipogenesis (CEBPα, Lep, Wnt10b), and decreased metabolism (PPARα) correlated with radiographic assessments. Gene expression changes suggest that rotator cuff tears lead to a dramatic molecular response in an attempt to maintain normal muscle tissue, increase adipogenesis, and decrease metabolism. Fat accumulation and muscle atrophy appear to stem from endogenous changes rather than from changes mediated by infiltrating cells. Results suggest that chronic unloading of muscle, induced by rotator cuff tear, disrupts muscle homeostasis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2808–2814, 2017.

     

Exercise following a short immobilization period is detrimental to tendon properties and joint mechanics in a rat rotator cuff injury model

Rotator cuff tears are a common clinical problem that can result in pain and disability. Previous studies in a rat model showed enhanced tendon to bone healing with postoperative immobilization. The objective of this study was to determine the effect of postimmobilization activity level on insertion site properties and joint mechanics in a rat model. Our hypothesis was that exercise following a short period of immobilization will cause detrimental changes in insertion site properties compared to cage activity following the same period of immobilization, but that passive shoulder mechanics will not be affected. We detached and repaired the supraspinatus tendon of 22 Sprague‐Dawley rats, and the injured shoulder was immobilized postoperatively for 2 weeks. Following immobilization, rats were prescribed cage activity or exercise for 12 weeks. Passive shoulder mechanics were determined, and following euthansia, tendon cross‐sectional area and mechanical properties were measured. Exercise following immobilization resulted in significant decreases compared to cage activity in range of motion, tendon stiffness, modulus, percent relaxation, and several parameters from both a structurally based elastic model and a quasi‐linear viscoelastic model. Therefore, we conclude that after a short period of immobilization, increased activity is detrimental to both tendon mechanical properties and shoulder joint mechanics, presumably due to increased scar production. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:841–845, 2010     

Latissimus dorsi tendon transfers for rotator cuff deficiency

Purpose:

Latissimus dorsi tendon transfers are increasingly being used around the shoulder. We aim to assess any improvement in pain and function following a latissimus dorsi tendon transfer for massive, irreparable postero-superior cuff deficiency.

Materials and Methods:

At our institution, between 1996 and 2009, 38 latissimus dorsi tendon transfer procedures were performed. Sixteen of these were for massive irreparable rotator cuff deficiency associated with pain and impaired function. All patients were evaluated by means of interview or postal questionnaire and case note review. Pain and function were assessed using the Stanmore percentage of normal shoulder assessment (SPONSA) score, visual analogue scale and Oxford Shoulder Score. Forward elevation was also assessed and a significant improvement was thought to correlate with the success of the procedure at stabilizing the humeral head upon elevation.

Results:

Mean follow-up time was 70 months. There was a significant reduction in pain on the visual analogue scale from 6.4 to 3.4 (P < 0.05), an improved SPONSA score from 32.5 to 57.5 (P < 0.05), and an improved Oxford Shoulder Score from 40.75 to 29.6 (P < 0.05). Forward elevation improved from 40° preoperatively to 75° postoperatively (P < 0.05).

Conclusion:

Our results add to the body of evidence that latissimus dorsi tendon transfers for irreparable postero-superior cuff deficiency in selected patients reduce pain and improve shoulder function in the medium term.

Level of Evidence:

Level 4.     

Mechanical properties of the long‐head of the biceps tendon are altered in the presence of rotator cuff tears in a rat model

Rotator cuff tears are disabling conditions that result in changes in joint loading and functional deficiencies. Clinically, damage to the long‐head of the biceps tendon has been found in conjunction with rotator cuff tears, and this damage is thought to increase with increasing tear size. Despite its importance, controversy exists regarding the optimal treatment for the biceps. An animal model of this condition would allow for controlled studies to investigate the etiology of this problem and potential treatment strategies. We created rotator cuff tears in the rat model by detaching single (supraspinatus) and multiple (supraspinatus + infraspinatus or supraspinatus + subscapularis) rotator cuff tendons and measured the mechanical properties along the length of the long‐head of the biceps tendon 4 and 8 weeks following injury. Cross‐sectional area of the biceps was increased in the presence of a single rotator cuff tendon tear (by ～150%), with a greater increase in the presence of a multiple rotator cuff tendon tear (by up to 220%). Modulus values decreased as much as 43 and 56% with one and two tendon tears, respectively. Also, multiple tendon tear conditions involving the infraspinatus in addition to the supraspinatus affected the biceps tendon more than those involving the subscapularis and supraspinatus. Finally, biceps tendon mechanical properties worsened over time in multiple rotator cuff tendon tears. Therefore, the rat model correlates well with clinical findings of biceps tendon pathology in the presence of rotator cuff tears, and can be used to evaluate etiology and treatment modalities. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:416–420, 2009     

Botulinum toxin is detrimental to repair of a chronic rotator cuff tear in a rabbit model

Re‐tear continues to be a problem after rotator cuff repair. Intramuscular botulinum toxin (Botox) injection can help optimize tension at the repair site to promote healing but could have an adverse effect on the degenerated muscle in a chronic tear. We hypothesized that Botox injection would improve repair characteristics without adverse effect on the muscle in a chronic rotator cuff tear model. The supraspinatus tendon of both shoulders in 14 rabbits underwent delayed repair 12 weeks after transection. One shoulder was treated with intramuscular Botox injection and the other with a saline control injection. Six weeks after repair, outcomes were based on biomechanics, histology, and magnetic resonance imaging. Botox‐treated repairs were significantly weaker (2.64 N) than control repairs (5.51 N, p = 0.03). Eighty percent of Botox‐treated repairs and 40% of control repairs healed with some partial defect. Fatty infiltration of the supraspinatus was present in all shoulders (Goutallier Grade 3 or 4) but was increased in the setting of Botox. This study provides additional support for the rabbit supraspinatus model of chronic cuff tear, showing consistent fatty infiltration. Contrary to our hypothesis, Botox had a negative effect on repair strength and might increase fatty infiltration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1152–1157, 2015.     

Glenoid cartilage mechanical properties decrease after rotator cuff tears in a rat model

Rotator cuff repairs are commonly performed to reduce pain and restore function. Tears are also treated successfully without surgical intervention; however, the effect that a torn tendon has on the glenohumeral cartilage remains unknown. Clinically, a correlation between massive rotator cuff tears and glenohumeral arthritis has often been observed. This may be due to a disruption in the balance of forces at the shoulder, resulting in migration of the humeral head and subsequently, abnormal loading of the glenoid. Our lab previously demonstrated changes in ambulation and intact tendon mechanical properties following supraspinatus and infraspinatus rotator cuff tendon tears in a rat model. Therefore, the purpose of this study was to investigate the effects of supraspinatus and infraspinatus rotator cuff tears on the glenoid cartilage. Nine rats underwent unilateral detachment of the supraspinatus and infraspinatus tendons and were sacrificed after 4 weeks. Cartilage thickness significantly decreased in the antero‐inferior region of injured shoulders. In addition, equilibrium elastic modulus significantly decreased in the center, antero‐superior, antero‐inferior, and superior regions. These results suggest that altered loading after rotator cuff injury may lead to damage to the joint with significant pain and dysfunction. Clinically, understanding the mechanical processes involved with joint damage will allow physicians to better advise patients. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1435–1439, 2012     

Relationship between muscle fatty infiltration and the biological characteristics and stimulation potential of tenocytes from rotator cuff tears

The healing after rotator cuff surgery is still dissatisfying, and increased muscle fatty infiltration even more impairs the healing success. To achieve sufficient healing after rotator cuff reconstructions, the use of growth factors may be one possibility. The aim of the study was to identify a possible relationship between fatty infiltration of the supraspinatus muscle and cellular biological characteristics and stimulation potential of tenocyte‐like cells (TLCs). TLCs of 3 donor groups differing in grade of muscle fatty infiltration were analyzed for their cellular characteristics and were stimulated with BMP‐2 or BMP‐7 in a 3D scaffold culture. The cell count and potency for self‐renewal were significantly decreased in TLCs from donors with high muscle fatty infiltration compared to the lower fatty infiltration groups. Cell count and collagen‐I expression as well as protein synthesis were stimulated by growth factors. Interestingly, TLCs of the high fatty infiltration group exhibited a weaker stimulation potential compared to the other groups. TLCs from donors with high muscle fatty infiltration generally revealed inferior characteristics compared to cells of lower fatty infiltration groups, which may be one reason for a weaker healing potential and may represent a possible starting point for the development of future treatment options. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:129–137, 2014.     

Shoulder muscle activation and coordination in patients with a massive rotator cuff tear: an electromyographic study

Adaptive muscle activation strategies following a massive rotator cuff tear (MRCT) are inadequately understood, and the relationship among muscles during everyday activities has not been considered. Thirteen healthy subjects comprised the control group, and 11 subjects with a MRCT the patient group. Upper limb function was assessed using the Functional Impairment test‐hand, neck, shoulder, and arm (FIT‐HaNSA). Electromyography (EMG) was recorded from 13 shoulder muscles, comprising five muscle groups, during a shelf‐lifting task. Mean FIT‐HaNSA scores were significantly lower in MRCT patients (p ≤ 0.001), reflecting a severe functional deficit. In MRCT patients, EMG signal amplitude was significantly higher for the biceps brachii‐brachioradialis (p < 0.001), upper trapezius‐serratus anterior (p = 0.025), muscle groups and for the latissimus dorsi (p = 0.010), and teres major (p = 0.007) muscles. No significant differences in the correlation among muscle groups were identified, pointing to an unchanged neuromuscular strategy following a tear. In MRCT patients, a reorganization of muscle activation strategy along the upper limb kinetic chain is aimed at reducing demand on the glenohumeral joint. Increased activation of the latissimus dorsi and teres major muscles is an attempt to compensate for the deficient rotator cuff. Re‐education towards an alternate neuromuscular control strategy appears necessary to restore function. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1140–1146, 2012