Objectives . Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as ‘fatty degeneration’. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified. Methods . A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation. Results . Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present. Conclusions . The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles. Cite this article: Bone Joint Res 2014;3:262–72

Disturbed muscular architecture, fatty infiltration and muscular atrophy remain irreversible in chronic rotator cuff tears (RCT) even after repair. Poly-[ADP-ribose]-polymerase 1 (PARP-1), a nuclear factor involved in DNA damage repair, has shown to be a key element in the up-regulation of early muscle inflammation, atrophy and fat deposition. We therefore hypothesized that the absence of PARP-1 would lead to a reduction in muscular architectural damage, early inflammation, atrophy and fatty infiltration subsequent to combined tenotomy and neurectomy in a PARP-1 knock-out mouse model.

PARP-1 knock-out (KO group) and standard wild type C57BL/6 (WT group) mice were randomly allocated into three different time points (1, 6 and 12 weeks, total n=72). In all mice the supraspinatus (SSP) and infraspinatus (ISP) tendons of the left shoulder were detached and the SSP muscle was denervated according to a recently established model. Macroscopic muscle weight analysis, retraction documentation using macroscopic suture, magnetic resonance imaging, immunohistochemistry gene expression analysis using real time qPCR (RTqPCR) and histology were used to assess the differences in muscle architecture, early inflammation, fatty infiltration and atrophy between knock out and wild type mice in the supraspinatus muscle.

The SSP did retract in both groups, however; the KO muscles and tendons retracted less than the WT muscles (2.1±21mm vs 3.4±0.41mm; p=0.02). Further assessment of muscle architecture demonstrated that the pennation angle was significantly higher in the KO groups at 6 and 12 weeks (28±5 vs 36±5 and 29±4 vs 34±3; p<0.0001). Combined Tenotomy and neurectomy resulted in a significant loss of muscle mass in both groups compared to the contralateral unoperated side (KO group 62±11% and WT group 52±11%, p=0.04) at 6 weeks. But at 12 weeks postoperatively, there was a significant increase in muscle mass to near normal levels in KO group compared to the WT group (14±6% and 42±7% lower muscle mass respectively; p<0.0001) and less fatty infiltration (12.5 ± 1.82% and 19.6 ± 1.96%, p=0.027). Immunohistochemistry revealed a significant decrease in the expression of inflammatory, apoptotic, adipogenic and muscular atrophy genes at both the 1 week and 6 weeks time points, but not at 12 weeks in the KO group compared to the WT group. This was confirmed by histology.

Our study is the first to show that knocking out PARP-1 leads to decreased loss of muscle architecture, early inflammation, fatty infiltration and atrophy after combined tenotomy and neurectomy of the rotator cuff muscle. Although the macroscopic muscles reaction to injury is similar in the first 6 weeks, its ability to regenerate is much greater in the PARP-1 group leading to a near normalization of the muscle substance and muscle weight, less retraction, and less fatty infiltration after 12 weeks.

Aging has been associated with decreases in muscle strength and bone quality. In elderly patients, paravertebral muscle atrophy is accompanied by vertebral osteoporosis. The purpose of this study was to use paravertebral injection of botulinum toxin-A (BTX) to investigate the effects of paravertebral muscle atrophy on lumbar vertebral bone quality. Forty 16-week-old female SD rats were randomly divided into four groups: (1) a control group (CNT); (2) a resection of erector spinae muscles group (RESM); (3) a botulinum toxin-A group (BTX) that was treated with local injection of 5U BTX into the paravertebral muscles bilaterally; and (4) a positive control group (OVX) that underwent bilateral ovariectomy. At 3 months post-surgery the lumbar vertebrae (L3 – L6) were collected. The BMDs of the RESM and BTX groups were significantly lower than that of the CNT group (P < 0.01). Micro-CT scans showed that rats in the three experimental groups had fewer trabeculae and trabecular connections than rats in the CNT group. The bone loss trend of the trabecular networks was most obvious in the OVX rats. Vertebral compression testing revealed that the three experimental groups had significantly lower maximum load, energy absorption, maximum stress, and elastic modulus values than the CNT group (P < 0.01), and these parameters were lowest in the OVX group (P < 0.05). Our results demonstrate that the new paravertebral muscle atrophy model using local BTX injection causes sufficient muscle atrophy and dysfunction to result in local lumbar vertebral bone loss and quality deterioration

Duchenne muscular dystrophy (DMD) is a prevalent childhood neuromuscular disease characterized by progressive skeletal and cardiac muscle degeneration due to dystrophin protein deficiency. Despite ongoing drug development efforts, no cure exists, with limited success in preclinical studies. To expedite DMD drug development, we introduce an innovative organ-on-a-chip (OOC) platform. This microfluidic device sustains up to six 3D patient-derived skeletal muscle tissues, enabling real-time evaluation of anti-DMD treatments. Our in vitro model recreates myotube integrity loss, a hallmark of DMD, by encapsulating myogenic precursors in a fibrin-composite matrix using a PDMS casting mold. Continuous contractile regimes mimic sarcolemmal instability, monitored through tissue contractibility and Creatine Kinase (CK) levels—an established marker of muscle damage. We further enhance our platform with a nanoplasmonic CK biosensor, enabling rapid, label-free, and real-time sarcolemmal damage assessment. Combining these elements, our work demonstrates the potential of OOCs in accelerating drug development for DMD and similar neuromuscular disorders

Anterior cruciate ligament reconstruction (ACLR) using a semitendinosus (ST) autograft, with or without gracilis (GR), results in donor muscle atrophy and varied tendon regeneration. The effects of harvesting these muscles on muscle moment arm and torque generating capacity have not been well described. This study aimed to determine between-limb differences (ACLR vs uninjured contralateral) in muscle moment arm and torque generating capacity across a full range of hip and knee motions. A secondary analysis of magnetic resonance imaging was undertaken from 8 individuals with unilateral history of ST-GR ACLR with complete ST tendon regeneration. All hamstring muscles and ST tendons were manually segmented. Muscle length (cm), peak cross-sectional area (CSA) (cm. 2. ), and volume (cm. 3. ) were measured in ACLR and uninjured contralateral limbs. OpenSim was used to simulate and evaluate the mechanical consequences of changes in normalised moment arm (m) and torque generating capacity (N.m) between ACLR and uninjured contralateral limbs. Compared to uninjured contralateral limbs, regenerated ST tendon re-insertion varied proximal (+) (mean = 0.66cm, maximum = 3.44cm, minimum = −2.17cm, range = 5.61cm) and posterior (+) (mean = 0.38cm maximum = 0.71cm, minimum = 0.02cm, range = 0.69cm) locations relative to native anatomical positions. Compared to uninjured contralateral limbs, change in ST tendon insertion point in ACLR limbs resulted in 2.5% loss in peak moment arm and a 3.4% loss in peak torque generating capacity. Accounting for changes to both max isometric force and ST moment arm, the ST had a 14.8% loss in peak torque generating capacity. There are significant deficits in ST muscle morphology and insertion points following ST-GR ACLR. The ST atrophy and insertion point migration following ACLR may affect force transmission and distribution within the hamstrings and contribute to persistent deficits in knee flexor and internal rotator strength

Abstract. Introduction. Skeletal muscle wasting is an important clinical issue following acute traumatic injury, and can delay recovery and cause permanent functional disability particularly in the elderly. However, the fundamental mechanisms involved in trauma-induced muscle wasting remain poorly defined and therapeutic interventions are limited. Objectives. To characterise local and systemic mediators of skeletal muscle wasting in elderly patients following acute trauma. Methods. Experiments were approved by a local NHS Research Ethics Committee and all participants provided written informed consent. Vastus lateralis biopsies and serum samples were taken from human male and female patients shortly after acute trauma injury in lower limbs (n=6; mean age 78.7±4.4 y) and compared to age-matched controls (n=6; mean age 72.6±6.3 y). Atrogenes and upstream regulators (MuRF1; MAFbx; IL6, TNFα, PGC-1α) mRNA expression was assessed in muscle samples via RT-qPCR. Serum profiling of inflammatory markers (e.g. IL6, TNFα, IL1β) was further performed via multiplex assays. To determine whether systemic factors induced by trauma directly affect muscle phenotype, differentiated primary human myotubes were treated in vitro with serum from controls or trauma patients (pooled; n=3 each) in the final 24 hours of differentiation. Cells were then fixed, stained for myogenin and imaged to determine minimum ferret diameter. Statistical significance was determined at P<0.05. Results. There was an increase in skeletal muscle mRNA expression for E3 ligase MAFbx and inflammatory cytokine IL-6 (4.6 and 21.5-fold respectively; P<0.05) in trauma patients compared to controls. Expression of myogenic determination factor MyoD and regulator of mitochondrial biogenesis PGC-1α was lower in muscle of trauma patients vs controls (0.5 and 0.39-fold respectively; P<0.05). In serum, trauma patients showed increased concentrations of circulating pro-inflammatory cytokines IL-6 (14.5 vs. 0.3 pg/ml; P<0.05) and IL-16 (182.7 vs. 85.2 pg/ml; P<0.05) compared to controls. Primary myotube experiments revealed serum from trauma patients induced atrophy (32% decrease in diameter) compared to control serum-treated cells (P<0.001). Conclusion. Skeletal muscle from patients following acute trauma injury showed greater expression of atrophy and inflammatory markers. Trauma patient serum exhibited higher circulating pro-inflammatory cytokine concentrations. Primary human myotubes treated with serum from trauma patients showed significant atrophy compared to healthy serum-treated controls. We speculate a mechanism(s) acting via circulating factors may contribute to skeletal muscle pathology following acute trauma. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

The function of the upper extremity is highly dependent on correlated motion of the shoulder. The shoulder can be affected by several diseases. The most common are: rotator cuff tear (RCT), shoulder instability, shoulder osteoarthritis and fractures. Rotator cuff disease is a common disorder. It has a high prevalence rate, causing high direct and indirect costs. The appropriate treatment for RCT is debated. The American Academy Orthopaedic Surgeons guidelines state that surgical repair is an option for patients with chronic, symptomatic full-thickness RCT, but the quality of evidence is unconvincing. Thus, the AAOS recommendations are inconclusive. We are performing a randomized controlled trial to compare surgical and conservative treatment of RCT, in term of functional outcomes, rotator cuff integrity, muscle atrophy and fatty degeneration. Shoulder instability occurs when the head of the upper arm bone is forced out of the shoulder socket. Shoulder instabilities have been classified according to the etiology, the direction of instability, or on combinations thereof. The Thomas and Matsen classification, which is currently the most commonly utilized classification, divides shoulder instability events into the traumatic, unidirectional, Bankart lesion, and surgery (TUBS) and the atraumatic, multidirectional, bilateral, rehabilitation, and capsular shift (AMBRI) categories. The acquired instability overstress surgery (AIOS) category was then added. Surgical procedures for shoulder instability includes arthroscopic capsuloplasty, remplissage, bone block procedure or Latarjet procedure. Reverse total shoulder arthroplasty (RTSA) represents a good solution for the management of patients with osteoarthritis or fracture of the proximal humerus, with associated severe osteoporosis and RC dysfunction

Sarcopenia is a progressive and generalized skeletal muscle disorder that involves loss of muscle mass and function. It is associated with increased adverse outcomes including falls, functional decline, frailty and mortality and affects 65% of people over the age of 65 more than half of people aged 80 and above. The factors that cause and worsen sarcopenia are categorised into two groups. The primary aetiological factor is ageing and the secondary factors include disease, physical inactivity, and poor nutrition. Sarcopenia is considered to be ‘primary' (or age-related) when no other specific cause is evident. However, a number of ‘secondary' factors may be present in addition to ageing. Sarcopenia can occur secondary to a systemic or inflammatory disease, including malignancy and organ failure. Physical inactivity is one of the major contributors to the development of sarcopenia, whether due to a sedentary lifestyle or to disease related immobility or disability. Furthermore, sarcopenia can develop as a result of inadequate protein consumption. Biomarkers are objective and quantifiable characteristics of physiological and pathophysiological processes. Biomarkers can be used to predict the development of sarcopenia in older susceptible adults and enable early interventions that can reduce the risk of physical disability, the co-morbidities associated with the loss of muscle mass and the poor health outcomes that result from sarcopenia. Non-invasive imaging technologies can be used as biomarkers to detect loss of skeletal muscle mass in sarcopenia include bone densitometry, computed tomography, ultrasound and magnetic resonance imaging. However, imaging requires sophisticated and expensive equipment that is not available in a resource poor setting. Therefore, markers of skeletal muscle strength and fitness and soluble biochemical markers in blood may be used as alternative biomarkers. Studies on sarcopenia have identified numerous soluble biochemical biomarkers. These biomarkers can be divided into two groups: “muscle-specific” and “non-muscle-specific” biomarkers. Since sarcopenia is associated with rapid skeletal muscle wasting, the skeletal muscle-specific isoform of troponin T may be considerate a useful biomarker of sarcopenia, since high troponin levels in blood are an expression of muscle wasting. Peptides derived from collagen type VI turnover may be potential biomarkers of sarcopenia. We have recently conducted a systematic review to summarize the data from recent mass-spectrometry based proteomic studies of the secretome of skeletal muscle cells in response to disease, exercise or metabolic stress in order to identify the proteins involved in muscle breakdown. Developing robust in vitro models for the study of sarcopenia using primary muscle cells is a high priority as is exploiting the in vitro models to understand catabolic and inflammatory processes and molecular mechanisms involved in sarcopenia. Co-cultures with adipose-derived and other cells may be used to screen for small molecules and biologicals capable of inhibiting the catabolic and inflammatory pathways involved in sarcopenia. This presentation reviews recent progress in this area and outlines opportunities for future research on sarcopenia

Objectives. Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. Methods. Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. Results. At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. Conclusions. GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred. Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57–65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1

The treatment of massive chronic tears is problematic. The re-tear rate following surgery for extensive cuff tears remains high, and there is little consensus regarding optimum treatment. To investigate the outcome of a cohort of patients who had open repair of an extensive cuff tear using the Leeds Kuff patch as an augment. A retrospective cohort study of consecutive patients with a massive cuff tear who had surgery in our regional elective orthopaedic centre over a two year period from January 2015 to Dec 2016. All patients followed identical rehabilitation protocols, supervised by physiotherapists with an interest in the shoulder. Outcomes assessment was undertaken at a minimum of 12 months by a registrar or physiotherapist who was not part of the treating team. Pre-op data collection included; range of motion, pain score, Oxford shoulder score (OSS), assessment of muscle atrophy on MRI. Data collection was completed in 15 patients. The mean age was 62 yrs (56 – 75). The mean pre-op OSS was 22, improving to a mean of 43. The range of motion and pain score improved. There were no intra-operative complications. One patient required a second surgery for evacuation of a haematoma at 10 days post op. One patient had an obvious re-tear at 4 months. Open rotator cuff repair with synthetic Kuff patch augmentation for chronic degenerative tears appears worthwhile when assessed at 12 months and they continuous to improve even at 18 months. This treatment method may be a useful option for patients > 70 years old

In patients with developmental dysplasia of the hip (DDH) chronic joint dislocation induces remodeling of the soft tissue with contractures, muscle atrophy, especially of the hip abductors muscles, leading to severe motor dysfunction, pain and disability (1). The aim pf the present work is to explore if a correct positioning of the prosthetic implants through 3D skeletal modeling surgical planning technologies and an adequate customized rehabilitation can be beneficial for patients with DDH in improving functional performance. The project included two branches: a methodology branch of software development for the muscular efficiency calculation, which was inserted in the Hip-Op surgical planning system (2), developed at IOR to allow surgical planning for patients with complex hip joint impairment; and a clinical branch which involved the use of the developed software as part of a clinical multicentric randomized trial. 50 patients with DDH were randomized in two groups: a simple surgical planning group and an advanced surgical planning with muscular study group. The latter followed a customized rehabilitation program for the strenghtening of hip abductor muscles. All patients were assessed before surgery (T0) and at 3 (T1) and 6 months (T2) postoperatively using clinical outcome (WOMAC, HHS, ROM, MMT, SF12, 10mt WT) and instrumental measures (Dynamometric MT). Pre- and post-operative musculoskeletal parameters obtained by the software (i.e., leg length discrepancy, hip abductor muscle lengths and lever arms) using Hip-Op during the surgical planning were considered. One Way ANOVA for ROM measurement showed a significant improvement at T2 in patients included in experimental group, as well as WOMAC, HHS and SF12 score. The Dynamometric MT score showed significant differences between at T2 (p<0.009). Spearman's rank correlation coefficients showed a significant correlation between both pre- and post-operative abductors lever arm (mm) and hip abductor muscle strength at T2 (ρ = −0.55 pre-op and ρ = −0.51 post-op, p p<0.012 and p<0.02 respectively) and between the operated pre-postoperative leg length variation (mm) and the hip abductor muscle strength (ρ = −0.55, p p<0.013). Results so far obtained showed an improvement of functional outcomes in patients undergoing hip replacement surgery who followed therapeutic diagnostic pathway sincluding a preoperative planning including the assessment of the abductiors lever arm and a dedicated rehabilitation program for the strenghtening of abductios. Particularly interesting is the inverse relationship between the strength of the hip abductor muscles and the variation of the postoperative abductor lever arm

The aim of this study was to perform a comprehensive evaluation of the changes in function from pre- to post-surgery in total and unilateral knee arthroplasty (UKA/TKA) patients. Twenty healthy (age 62.4 ±5.9, 11 male), 14 UKA (age 60.9 ±10.1, 8 male) and 17 TKA (age 67.2 ±8.1, 9 male) patients were studied. KA patients were assessed four weeks pre- and six months post-operation. Measures of perceived pain and function were collected using Oxford Knee Score (OKS) questionnaire. Tests of objective function included joint range of motion (RoM), ultrasound imaging, and 3-D motion analysis/inverse modelling from gait and sit-stand. An optimal set of variables was used to classify KA function using the Cardiff DST method. Pre-KA and healthy individuals were accurately classified (96%). Post-operation questionnaire measures of function improved for both UKA and TKA groups. However, observed measures of RoM, muscle atrophy and gait had only limited gains. This resulted in 57% of UKA and only 27% of TKA patients being classified as healthy post-operation. The results of this study show that 6 months post-surgery UKA patients had higher function than TKA. Using statistical approaches to combine functional assessments has provided an accurate platform to classify function and estimate changes from pre- to post-surgery. The clinical application of this tool requires further investigation and comparison to commonly used clinical techniques

Objectives

The evidence base to inform the management of Achilles tendon rupture is sparse. The objectives of this research were to establish what current practice is in the United Kingdom and explore clinicians’ views on proposed further research in this area. This study was registered with the ISRCTN (ISRCTN68273773) as part of a larger programme of research.

The aim of this randomised, controlled in vivo study in an ovine model was to investigate the effect of cylic pneumatic pressure on fracture healing. We performed a transverse osteotomy of the right radius in 37 sheep. They were randomised to a control group or a treatment group where they received cyclic loading of the osteotomy by the application of a pressure cuff around the muscles of the proximal forelimb. Sheep from both groups were killed at four or six weeks. Radiography, ultrasonography, biomechanical testing and histomorphometry were used to assess the differences between the groups. The area of periosteal callus, peak torsional strength, fracture stiffness, energy absorbed over the first 10° of torsion and histomorphometric analysis all showed that the osteotomies treated with the cyclic pneumatic pressure at four weeks were not significantly different from the control osteotomies at six weeks.