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The effect of unloading on gene expression of healthy and injured rotator cuffs.

ABSTRACT: Tendon unloading following rupture of one of the rotator cuff tendons can induce alterations in muscle physiology and tendon structure, which can subsequently affect reparability and healing potential. Yet little is known about the effects of muscle and tendon unloading on the molecular response of the rotator cuff. We determined the effect of mechanical unloading on gene expression and morphology of healthy supraspinatus tendons and muscles, and the same muscles after acute injury and repair. Mechanical unloading was achieved by tenotomy and/or botulinum toxin A (BTX) chemical denervation in a rat rotator cuff model of injury and repair. Gene expression profiles varied across regions of the muscle, with the greatest changes seen in the distal aspect of the muscle for most genes. Myogenic and adipogenic genes were upregulated in muscle when unloaded (tenotomy and BTX). Tendon injury, with and without repair, resulted in upregulation of fibrosis- and tendon-specific gene expression. The expression of scleraxis, a transcription factor necessary for tendon development, was upregulated in response to injury and repair. In summary, tendon detachment and repair had the greatest effect on tendon gene expression, while unloading had the greatest effect on muscle gene expression.

SUBMITTER: Killian ML

PROVIDER: S-EPMC3690165 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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The effect of unloading on gene expression of healthy and injured rotator cuffs.

Killian M L ML Lim C T CT Thomopoulos S S Charlton N N Kim H M HM Galatz L M LM

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20130318 8

Tendon unloading following rupture of one of the rotator cuff tendons can induce alterations in muscle physiology and tendon structure, which can subsequently affect reparability and healing potential. Yet little is known about the effects of muscle and tendon unloading on the molecular response of the rotator cuff. We determined the effect of mechanical unloading on gene expression and morphology of healthy supraspinatus tendons and muscles, and the same muscles after acute injury and repair. M ...[more]

PMID: 23508698

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Project description:BackgroundNormative data are essential to the evaluation of shoulder function. The purposes of this study were to establish a normative database of isometric shoulder strength measured in asymptomatic individuals verified to have intact rotator cuffs and to determine the effect of asymptomatic rotator cuff tears on shoulder strength.MethodsTwo hundred and thirty-seven volunteers with no shoulder pain or history of shoulder injury were screened with ultrasonography bilaterally for rotator cuff tears and then underwent isometric strength measurements for abduction in the scapular plane and external rotation. Statistical analysis was performed to evaluate the effect of age, body habitus, hand dominance, and the presence of a rotator cuff tear on shoulder strength.ResultsOf the 237 volunteers, forty-one were found to have a torn rotator cuff in at least one shoulder. The prevalence of rotator cuff tears was 0% for the subjects between forty and forty-nine years old; 10%, between fifty and fifty-nine years old; 20%, between sixty and sixty-nine years old; and 40.7% for those seventy years old or older. Both abduction strength and external rotation strength in the male subjects showed an age-dependent decrease, whereas only abduction strength showed an age-dependent decrease in the female subjects. In multiple regression analysis, age and weight were the most important predictors of abduction strength and external rotation strength, respectively. In the shoulders with a large-to-massive full-thickness rotator cuff tear, abduction strength was significantly decreased (p = 0.007). Additionally, the ratio of abduction strength to external rotation strength was significantly decreased in the shoulders with a large-to-massive full-thickness tear compared with the shoulders with an intact rotator cuff (p < 0.001).ConclusionsThere is a high prevalence of rotator cuff tears in elderly asymptomatic individuals. Asymptomatic shoulders with a large-to-massive full-thickness rotator cuff tear have significantly decreased abduction strength. When there is a substantial decrease in abduction strength in relation to external rotation strength, the presence of an asymptomatic full-thickness tear should be suspected in that shoulder. Previous studies establishing normative values for isometric shoulder strength may have been skewed by the presence of asymptomatic rotator cuff tears in elderly subgroups.

Project description:BackgroundTo address the need for more objective and quantitative measures of tendon healing in research studies, we intend to use computed tomography (CT) with implanted radiopaque markers on the repaired tendon to measure tendon retraction following rotator cuff repair. In our small prior study, retraction at 1-year follow-up averaged 16.1± 5.3 mm and exceeded 10.0 mm in 12 of 13 patients, and thus tendon retraction appears to be a common clinical phenomenon. This study's objectives were to assess, using 5 longitudinal CT scans obtained over 1 year following rotator cuff repair, the variability in glenohumeral positioning because of pragmatic variations in achieving perfect arm repositioning and to estimate the associated measurement variability in bone-to-tendon marker length measurements.MethodsForty-eight patients underwent rotator cuff repair with intraoperative placement of radiopaque tendon markers at the repair site. All patients had a CT scan with their arms at the side on the day of surgery and at 3, 12, 26, and 52 weeks postoperatively. Glenohumeral position (defined by the orientation and distance of the humerus with respect to the scapula) and bone-to-tendon marker lengths were measured from each scan. Within-patient variation in glenohumeral position measurements was described by their pooled within-patient standard deviations (SDs), and variation in bone-to-tendon marker lengths by their standard errors of measurement (SEMs) and 95% confidence level minimally detectable distances (MDD95) and changes (MDC95).ResultsThe mean glenohumeral orientation from the 5 longitudinal CT scans averaged across the 48 patients was 12.6° abduction, 0.4° flexion, and -0.1° internal rotation. Within-patient SDs (95% confidence intervals) of glenohumeral orientation were 3.0° (2.7°-3.4°) in extension/flexion, 5.2° (4.6°-5.8°) in abduction/adduction, and 8.2° (7.3°-9.2°) in internal/external rotation. The SDs of glenohumeral distances were less than 1 mm in any direction. The estimated SEMs of bone-to-tendon lengths were consistent with a common value of 2.4 mm for any of the tendon markers placed across the repair, with MDD95 of 4.7 mm and MDC95 of 6.7 mm.ConclusionApparent tendon retraction of 5 mm or more, when measured as the distance from a tendon marker's day of surgery location to its new location on a volumetrically registered longitudinal CT scan, may be considered above the usual range of measurement variation. Tendon retraction measured using implanted radiopaque tendon markers offers an objective and sufficiently reliable means for quantifying the commonly expected changes in structural healing following rotator cuff repair.

Project description:Nitric oxide (NO), produced by NO-synthases via L-arginine oxidation, is an essential trigger for signaling processes involved in structural and metabolic changes in muscle fibers. Recently, it was shown that L-arginine administration prevented the decrease in levels of the muscle cytoskeletal proteins, desmin and dystrophin, in rat soleus muscle after 14 days of hindlimb unloading. Therefore, in this study, we investigated the effect of L-arginine administration on the degree of atrophy changes in the rat soleus muscles under unloading conditions, and on the content, gene expression, and phosphorylation level of titin, the giant protein of striated muscles, able to form a third type of myofilaments-elastic filaments. A 7-day gravitational unloading [hindlimb suspension (HS) group] resulted in a decrease in the soleus weight:body weight ratio (by 31.8%, p < 0.05), indicating muscle atrophy development. The content of intact titin (T1) decreased (by 22.4%, p < 0.05) and the content of proteolytic fragments of titin (T2) increased (by 66.7%, p < 0.05) in the soleus muscle of HS rats, compared to control rats. The titin gene expression and phosphorylation level of titin between these two groups were not significantly different. L-Arginine administration under 7-day gravitational unloading decreased the degree of atrophy changes and also prevented the decrease in levels of T1 in the soleus muscle as compared to HS group. Furthermore, L-arginine administration under unloading resulted in increased titin mRNA level (by 76%, p < 0.05) and decreased phosphorylation level of T2 (by 28%, p < 0.05), compared to those in the HS group. These results suggest that administration of L-arginine, the NO precursor, under unloading decreased the degree of atrophy changes, increased gene expression of titin and prevented the decrease in levels of T1 in the rat soleus muscle. The results can be used to search for approaches to reduce the development of negative changes caused by gravitational unloading in the muscle.

Project description:Detrimental changes in the composition and function of rotator cuff (RC) muscles are hallmarks of RC disease progression. Previous studies have demonstrated both atrophic and degenerative muscle loss in advanced RC disease. However, the relationship between gene expression and RC muscle pathology remains poorly defined, in large part due to a lack of studies correlating gene expression to tissue composition. Therefore, the purpose of this study was to determine how tissue composition relates to gene expression in muscle biopsies from patients undergoing reverse shoulder arthroplasty (RSA). Gene expression related to myogenesis, atrophy and cell death, adipogenesis and metabolism, inflammation, and fibrosis was measured in 40 RC muscle biopsies, including 31 biopsies from reverse shoulder arthroplasty (RSA) cases that had available histology data and 9 control biopsies from patients with intact RC tendons. After normalization to reference genes, linear regression was used to identify relationships between gene expression and tissue composition. Hierarchical clustering and principal component analysis (PCA) identified unique clusters, and fold-change analysis was used to determine significant differences in expression between clusters. We found that gene expression profiles were largely dependent on muscle presence, with muscle fraction being the only histological parameter that was significantly correlated to gene expression by linear regression. Similarly, samples with histologically-confirmed muscle distinctly segregated from samples without muscle. However, two sub-groups within the muscle-containing RSA biopsies suggest distinct phases of disease, with one group expressing markers of both atrophy and regeneration, and another group not significantly different from either control biopsies or biopsies lacking muscle. In conclusion, this study provides context for the interpretation of gene expression in heterogeneous and degenerating muscle, and provides further evidence for distinct stages of RC disease in humans.

Dataset Information

The effect of unloading on gene expression of healthy and injured rotator cuffs.

Publications

The effect of unloading on gene expression of healthy and injured rotator cuffs.

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