Meniscus Tears in Elite Athletes: Treatment Considerations, Clinical Outcomes, and Return to Play.

PURPOSE OF REVIEW: Management of meniscal injuries in the elite athlete is a difficult problem secondary to the high demands of athletic competition, the need for a timely return to sport, and the desire to maximize performance over time. The purpose of this review is to provide an up-to-date summary on the current literature and trends regarding the management of meniscus injuries with a special consideration for elite athletes. RECENT FINDINGS: Historically, partial meniscectomy has been the primary treatment option for meniscus injuries. However, in recent years there has been an increased emphasis on meniscus preservation due to the increased risk of cartilage degeneration over time. Moreover, while partial meniscectomy still provides a quicker return to sport (RTS), recent literature has demonstrated similar rates of RTS and return to pre-injury levels between partial meniscectomy and meniscus repair. In the setting of symptomatic meniscal deficiency, meniscus allograft transplantation has become an increasingly utilized salvage procedure with promising yet variable outcomes on the ability to withstand elite competition. Currently, there is no uniform approach to treating meniscal injuries in elite athletes. Therefore, an individualized approach is required with consideration of the meniscus tear type, location, concomitant injuries, athlete expectations, rehabilitation timeline, and desire to prevent or delay knee osteoarthritis. In athletes with anatomically repairable tears, meniscus repair should be performed given the ability to restore native anatomy, provide high rates of RTS, and mitigate long-term chondral damage. However, partial meniscectomy can be indicated for unrepairable tears.

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury.

BACKGROUND: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. PURPOSE: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of ß-agonism on this novel process. STUDY DESIGN: Controlled laboratory study. METHODS: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a ß-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with ß-agonists and dimethyl sulfoxide. RESULTS: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a ß-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. CONCLUSION: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with ß-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. CLINICAL RELEVANCE: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

Distinct human stem cell subpopulations drive adipogenesis and fibrosis in musculoskeletal injury.

Fibroadipogenic progenitors (FAPs) maintain healthy skeletal muscle in homeostasis but drive muscle degeneration in chronic injuries by promoting adipogenesis and fibrosis. To uncover how these stem cells switch from a pro-regenerative to pro-degenerative role we perform single-cell mRNA sequencing of human FAPs from healthy and injured human muscles across a spectrum of injury, focusing on rotator cuff tears. We identify multiple subpopulations with progenitor, adipogenic, or fibrogenic gene signatures. We utilize full spectrum flow cytometry to identify distinct FAP subpopulations based on highly multiplexed protein expression. Injury severity increases adipogenic commitment of FAP subpopulations and is driven by the downregulation of DLK1. Treatment of FAPs both in vitro and in vivo with DLK1 reduces adipogenesis and fatty infiltration, suggesting that during injury, reduced DLK1 within a subpopulation of FAPs may drive degeneration. This work highlights how stem cells perform varied functions depending on tissue context, by dynamically regulating subpopulation fate commitment, which can be targeted improve patient outcomes after injury.

Algorithmic assessment of shoulder function using smartphone video capture and machine learning.

Tears within the stabilizing muscles of the shoulder, known as the rotator cuff (RC), are the most common cause of shoulder pain-often presenting in older patients and requiring expensive advanced imaging for diagnosis. Despite the high prevalence of RC tears within the elderly population, there is no previously published work examining shoulder kinematics using markerless motion capture in the context of shoulder injury. Here we show that a simple string pulling behavior task, where subjects pull a string using hand-over-hand motions, provides a reliable readout of shoulder mobility across animals and humans. We find that both mice and humans with RC tears exhibit decreased movement amplitude, prolonged movement time, and quantitative changes in waveform shape during string pulling task performance. In rodents, we further note the degradation of low dimensional, temporally coordinated movements after injury. Furthermore, a logistic regression model built on our biomarker ensemble succeeds in classifying human patients as having a RC tear with > 90% accuracy. Our results demonstrate how a combined framework bridging animal models, motion capture, convolutional neural networks, and algorithmic assessment of movement quality enables future research into the development of smartphone-based, at-home diagnostic tests for shoulder injury.

A Tool for Low-Cost, Quantitative Assessment of Shoulder Function Using Machine Learning.

Tears within the stabilizing muscles of the shoulder, known as the rotator cuff (RC), are the most common cause of shoulder pain-often presenting in older patients and requiring expensive, advanced imaging for diagnosis1-4. Despite the high prevalence of RC tears within the elderly population, there are no accessible and low-cost methods to assess shoulder function which can eschew the barrier of an in-person physical exam or imaging study. Here we show that a simple string pulling behavior task, where subjects pull a string using hand-over-hand motions, provides a reliable readout of shoulder health across animals and humans. We find that both mice and humans with RC tears exhibit decreased movement amplitude, prolonged movement time, and quantitative changes in waveform shape during string pulling task performance. In rodents, we further note the degradation of low dimensional, temporally coordinated movements after injury. Furthermore, a predictive model built on our biomarker ensemble succeeds in classifying human patients as having a RC tear with >90% accuracy. Our results demonstrate how a combined framework bridging task kinematics, machine learning, and algorithmic assessment of movement quality enables future development of smartphone-based, at-home diagnostic tests for shoulder injury.

Relationship Between Preoperative Shoulder Osteoarthritis Severity Score and Postoperative PROMIS-UE Score After Rotator Cuff Repair.

Background: Mild to moderate glenohumeral joint osteoarthritis is a common finding among patients who are evaluated for rotator cuff tears. However, the impact of preoperative shoulder joint degeneration on patient-reported outcomes after rotator cuff repair (RCR) is not well-established. Purpose: To apply the magnetic resonance imaging (MRI)-based Shoulder Osteoarthritis Severity (SOAS) score to the evaluation of patients undergoing RCR and determine the relationship between preoperative shoulder pathology present on MRI and postoperative Patient-Reported Outcomes Measurement Information System-Upper Extremity (PROMIS-UE) scores. Study Design: Case-control study; Level of evidence, 3. Methods: Seventy-one MRI scans corresponding to 71 patients were analyzed by 2 independent reviewers and scored using the SOAS criteria. Intraclass correlation coefficients were calculated for total SOAS score as well as for each subscore. Spearman correlations were calculated between averaged SOAS scores, patient characteristics, and PROMIS-UE scores. Linear regression analysis was performed between the independent variables of patient age, sex, body mass index, and significant SOAS score components determined by univariate analysis with the dependent variable of PROMIS-UE score. Significance was defined as P < .05 for univariate analyses and < .0125 for multivariate analyses using the Bonferroni correction. Results: The mean PROMIS-UE score of this cohort was 51.5 ± 7.4, while the mean total SOAS score was 21.5 ± 8.4. There was a negative correlation between total SOAS score and postoperative PROMIS-UE score (r = -0.24; P = .040). Both cartilage wear (r = -0.33; P = .0045) and acromioclavicular joint degeneration (r = -0.24; P = .048) individually demonstrated negative correlations with PROMIS-UE score. When a multivariate linear regression with Bonferroni correction was applied to the significant variables identified in univariate analysis along with patient characteristics, none were independently correlated with PROMIS-UE score. Conclusion: In this cohort of patients undergoing RCR, increasing preoperative total SOAS score was predictive of lower postoperative PROMIS-UE scores. SOAS subscores with the strongest negative correlations with PROMIS-UE scores included cartilage wear and acromioclavicular joint degeneration. The cartilage subscore was negatively correlated with PROMIS-UE scores independent of patient factors in multivariate analysis.

National Football League (NFL) quarterbacks who were multisport high school athletes have better in-season performance statistics and career success.

OBJECTIVES: To determine (1) the proportion of National Football League (NFL) quarterbacks (QBs) who were multisport high school athletes (2) whether performance metrics in NFL QBs differed by playing multiple high school sports versus the single sport of football. METHODS: A comprehensive online search identified NFL QBs from 1995 to 2020, classifying them as single or multisport high school athletes. Performance data were collected for regular season and playoffs when applicable and were calculated as rates. Regular season comparisons were limited to players playing at least eight games. Accolades (Pro Bowls, MVP awards, and Super Bowl victories) were also recorded. Mann-Whitney U was utilized to compare performance metrics between multisport and single sport athletes. RESULTS: 403 QBs (223, 55.3% multisport) were included. In the regular season, multisport QBs played in more games (median 6.8, IQR 4-10.6 vs median 5, IQR 2.5-8.3; p = 0.0001), and had higher touchdowns/game (median 0.87, IQR 0.5-1.25 vs median 0.67, IQR 0.42-1; p = 0.0063), pass yards/game (median 159.4, IQR 103.9-206.7 vs median 139.4, IQR 96.3-179.6; p = 0.0392), and QB rating (median 78.5, IQR 69.4-85.2 vs median 74.4, IQR 66.7-81.2; p = 0.0063). There were no differences in pass completion %, interceptions/game, or rush yards/game. Multisport QBs played in more playoff games (median 0.5, IQR 0.22-0.81 vs median 0.33, IQR 0.2-0.62; p = 0.027), and had more Pro Bowl appearances, MVP awards, and Super Bowl victories per athlete (p < 0.05). CONCLUSION: Over half of NFL QBs played multiple high school sports. Multisport involvement is associated with benefits in regular season including a higher proportion of games played, and more touchdowns/game, pass yards/game, and QB rating. Playing multiple sports was also associated with playing more playoff games and having more Pro Bowl appearances, MVP awards, and Super Bowl victories. This data supports the benefits of youth multisport training.

Muscle-Derived Beige Adipose Precursors Secrete Promyogenic Exosomes That Treat Rotator Cuff Muscle Degeneration in Mice and Are Identified in Humans by Single-Cell RNA Sequencing.

BACKGROUND: Muscle atrophy, fibrosis, and fatty infiltration are common to a variety of sports-related and degenerative conditions and are thought to be irreversible. Fibroadipogenic progenitors (FAPs) are multipotent resident muscle stem cells with the capacity to differentiate into fibrogenic as well as white and beige adipose tissue (BAT). FAPs that have assumed a BAT differentiation state (FAP-BAT) have proven efficacious in treating muscle degeneration in numerous injury models. PURPOSE: To characterize the subpopulation of murine FAPs with FAP-BAT activity, determine whether their promyogenic effect is mediated via exosomes, and analyze human FAPs for an analogous promyogenic exosome-rich subpopulation. STUDY DESIGN: Controlled laboratory study. METHODS: FAPs from UCP1 reporter mice were isolated via fluorescence-activated cell sorting and sorted according to the differential intensity of the UCP1 signal observed: negative for UCP1 (UCP1-), intermediate intensity (UCP1+), and high intensity (UCP1++). Bulk RNA sequencing was performed on UCP1-, UCP1+, and UCP1++ FAPs to evaluate distinct characteristics of each population. Exosomes were harvested from UCP1++ FAP-BAT exosomes (Exo-FB) as well as UCP1- non-FAP-BAT exosomes (Exo-nFB) cells using cushioned-density gradient ultracentrifugation and used to treat C2C12 cells and mouse embryonic fibroblasts in vitro, and the myotube fusion index was assessed. Exo-FB and Exo-nFB were then used to treat wild type C57B/L6J mice that had undergone a massive rotator cuff tear. At 6 weeks mice were sacrificed, and supraspinatus muscles were harvested and analyzed for muscle atrophy, fibrosis, fatty infiltration, and UCP1 expression. Single-cell RNA sequencing was then performed on FAPs isolated from human muscle that were treated with the beta-agonist formoterol or standard media to assess for the presence of a parallel promyogenic subpopulation of FAP-BAT cells in humans. RESULTS: Flow cytometry analysis of sorted UCP1 reporter mouse FAPs revealed a trimodal distribution of UCP1 signal intensity, which correlated with 3 distinct transcriptomic profiles characterized with bulk RNA sequencing. UCP1++ cells were marked by high mitochondrial gene expression, BAT markers, and exosome surface makers; UCP1- cells were marked by fibrogenic markers; and UCP1+ cells were characterized differential enrichment of white adipose tissue markers. Exo-FB treatment of C2C12 cells resulted in robust myotube fusion, while treatment of mouse embryonic fibroblasts resulted in differentiation into myotubes. Treatment of cells with Exo-nFB resulted in poor myotube formation. Mice that were treated with Exo-FB at the time of rotator cuff injury demonstrated markedly reduced muscle atrophy and fatty infiltration as compared with treatment with Exo-nFB or phosphate-buffered saline. Single-cell RNA sequencing of human FAPs from the rotator cuff revealed 6 distinct subpopulations of human FAPs, with one subpopulation demonstrating the presence of UCP1+ beige adipocytes with a distinct profile of BAT, mitochondrial, and extracellular vesicle-associated markers. CONCLUSION: FAP-BAT cells form a subpopulation of FAPs with upregulated beige gene expression and exosome production that mediate promyogenic effects in vitro and in vivo, and they are present as a transcriptomically similar subpopulation of FAPs in humans. CLINICAL RELEVANCE: FAP-BAT cells and their exosomes represent a potential therapeutic avenue for treating rotator cuff muscle degeneration.

Rotator Cuff Tear Size Regulates Fibroadipogenic Progenitor Number and Gene Expression Profile in the Supraspinatus Independent of Patient Age.

BACKGROUND: Fatty infiltration of rotator cuff muscle is a limiting factor in the success of repairs. Fibroadipogenic progenitors (FAPs) are a population of stem cells within the rotator cuff that can differentiate into white adipocytes, fibroblasts, and beige adipocytes. The effects of patient age and rotator cuff tendon tear size on the number, differentiation patterns, and gene expression profiles of FAPs have not yet been analyzed. PURPOSE: To determine if patient age and rotator cuff tear size independently regulate FAP number, differentiation patterns, and gene expression profiles. STUDY DESIGN: Controlled laboratory study. METHODS: Supraspinatus muscle samples were collected from 26 patients between the ages of 42 and 76 years with partial- or full-thickness rotator cuff tears. FAPs were quantified using fluorescence-activated cell sorting. Gene expression analysis was performed across a custom 96-gene panel using NanoString. In vitro differentiation assays of FAPs were conducted using adipogenic, fibrogenic, and beige-inducing (amibegron-treated) media, and quantitative polymerase chain reaction was used to assess gene expression differences between adipogenic and amibegron media conditions. Multivariable linear regressions were performed using Stata to independently analyze the effects of age and rotator cuff tear size on FAP number, differentiation, and gene expression. RESULTS: Increasing age and tear size were independently correlated with increased FAP number (ßage = 0.21, P = .03; ßtear size = 3.86, P = .05). There was no clear association between age and gene expression of freshly sorted FAPs. Under adipogenic and fibrogenic media conditions, increasing age and tear size were independently associated with increased adipogenic and fibrogenic differentiation of FAPs. Under amibegron treatment conditions, age positively correlated with increased beige differentiation (ß = 1.03; P < .0001), while increasing tear size showed a trend toward decreased beige differentiation (ß = -4.87; P = .1). When gene expression patterns between adipogenic and amibegron media conditions were compared, larger tear size strongly inhibited beige gene expression, while advanced age did not. CONCLUSION: Patient age and rotator cuff tear size independently regulated FAP number, differentiation, and gene expression. Age and tear size were positively correlated with increased FAP number and fibrogenic/adipogenic differentiation. Advancing patient age did not limit FAP beige differentiation and gene expression, while increasing rotator cuff tear size strongly inhibited these processes.

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury.

BACKGROUND CONTEXT: The association between low back pain and lumbar disc degeneration is not fully characterized. One potentially overlooked factor of this process is the lumbar multifidus, which plays a role in segmental stabilization and locomotion. Previous reports have shown multifidus degeneration to be associated with disc degeneration. The goal of this study was to develop a mouse model of advanced lumbar disc degeneration to recapitulate the pathology of the human multifidus in patients with lumbar disc degeneration and low back pain. METHODS: C57BL/6 mice underwent a left anterolateral approach to the lumbar spine and disc puncture with a micro scalpel at L5/6 and L6/S1. Mice underwent behavioral analysis and functional gait testing. A subset of mice underwent 14T T2-weighted MRI to assess disc degeneration and paraspinal muscle quality. At 6 and 15 weeks, mice were sacrificed, and the multifidus muscles were harvested and divided into proximal and distal segments relative to disc injury. Histological analysis was performed to assess muscle degeneration, fiber type, and macrophage density. Fibroadipogenic progenitors (FAPs) were isolated for gene expression analysis with qPCR. RESULTS: MRI demonstrated decreased intervertebral disc signal and paraspinal muscle atrophy at 6 weeks, with progressive degeneration and atrophy at 15 weeks. Disc injury resulted in delayed functional recovery and impaired gait. Histology demonstrated progressive multifidus fibrofatty degeneration between 6 and 15 weeks. CD68+ macrophage density was increased at 6 weeks but not 15 weeks. FAPs exhibited increased fibrotic and adipogenic gene expression at 6 weeks compared to sham with less of a difference in gene expression by 15 weeks. CONCLUSIONS: We have developed a mouse model of disc injury-mediated paraspinal muscle degeneration that recapitulates features of degenerative muscle pathology observed in patients with lumbar disc degeneration, and highlights the role of FAPs in mediating fibrofatty muscle degeneration after disc injury.

A Mouse Model of Delayed Rotator Cuff Repair Results in Persistent Muscle Atrophy and Fatty Infiltration.

BACKGROUND: Rotator cuff (RC) tears are common tendon injuries seen in orthopaedic patients. Successful repair of large and massive RC tears remains a challenge due to our limited understanding of the pathophysiological features of this injury. Clinically relevant small animal models that can be used to study the pathophysiological response to repair are limited by the lack of chronic repair models. PURPOSE: To develop a highly clinically relevant mouse model of delayed RC repair. STUDY DESIGN: Controlled laboratory study. METHODS: Three-month-old C57BL/6J mice underwent unilateral supraspinatus (SS) and infraspinatus (IS) tendon tear with immediate, 2-week delayed, or 6-week delayed tendon repair. Animals with no repair or sham surgery served as controls. Gait analysis was conducted to measure shoulder function at 2 weeks and 6 weeks after surgery. Animals were sacrificed 6 weeks after the last surgery. Shoulder joint, SS, and IS muscles were harvested and analyzed histologically. Ex vivo mechanical testing of intact and repaired SS and IS tendons was conducted. Reverse-transcriptase polymerase chain reaction was performed on SS and IS muscles to quantify atrophy, fibrosis, and fatty infiltration-related gene expression. RESULTS: Histological and tendon mechanical testing showed that torn tendons could be successfully repaired as late as 6 weeks after transection. However, significant atrophy and fatty infiltration of muscle, with impaired shoulder function, were persistent in the 6-week delayed repair group. Shoulder function correlated with the severity of RC muscle weight loss and fatty infiltration. CONCLUSION: We successfully developed a clinically relevant mouse model of delayed RC repair. Six-week delayed RC repair resulted in persistent muscle atrophy and fatty infiltration with inferior shoulder function compared with acute repair. CLINICAL RELEVANCE: Our novel mouse model could serve as a powerful tool to understand the pathophysiological and cellular/molecular mechanisms of RC muscle and tendon degeneration, eventually improving our strategies for treating and repairing RC tears.

Muscle stem cell activation in a mouse model of rotator cuff injury.

Rotator cuff (RC) tears are frequently complicated by muscle atrophy. Muscle stem cells (MuSCs) repair damaged myofibers following injury, but their role in the prevention or pathogenesis of atrophy following RC tears remains undefined. We hypothesized that the RC MuSC population would be affected by supraspinatus (SS) and infraspinatus (IS) tendon transection (TT) compared to uninjured muscle in a mouse model of RC tear. C57BL6/J mice underwent unilateral SS and IS TT and contralateral sham surgery. At 3, 8, or 14 weeks after injury, mice were euthanized, and SS and IS were harvested for FACS sorting of CD31-/CD45-/Sca1-/ITGa7+/VCAM+ MuSCs or histological analysis. Ki-67+ MuSCs from injured muscle increased 3.4-fold at 3 weeks (p = 0.03) and 8.1-fold at 8 weeks (p = 0.04) following TT injury, but returned to baseline by 14 weeks (p = 0.91). Myod1 remained upregulated 3.3-fold at 3 weeks (p = 0.03) and 2.0-fold at 14 weeks (p = 0.0003), respectively. Myofiber cross-sectional area was decreased at both 3 and 14 weeks after injury, but the number of MuSCs per fiber remained relatively constant at 3 (p = 0.3) and 14 (p = 0.6) weeks after TT. In this study, we characterized the longitudinal effect of RC tendon injury on the MuSC population in supraspinatus and infraspinatus muscles. MuSCs are transiently activated, and are not depleted, in spite of persistent muscle atrophy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1370-1376, 2018.

Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears.

Previous studies have suggested that macrophage-mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon-nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFα and TGF-ß1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co-staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA-mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1539-1547, 2017.

TGF-ß Small Molecule Inhibitor SB431542 Reduces Rotator Cuff Muscle Fibrosis and Fatty Infiltration By Promoting Fibro/Adipogenic Progenitor Apoptosis.

Rotator cuff tears represent a large burden of muscle-tendon injuries in our aging population. While small tears can be repaired surgically with good outcomes, critical size tears are marked by muscle atrophy, fibrosis, and fatty infiltration, which can lead to failed repair, frequent re-injury, and chronic disability. Previous animal studies have indicated that Transforming Growth Factor-ß (TGF-ß) signaling may play an important role in the development of these muscle pathologies after injury. Here, we demonstrated that inhibition of TGF-ß1 signaling with the small molecule inhibitor SB431542 in a mouse model of massive rotator cuff tear results in decreased fibrosis, fatty infiltration, and muscle weight loss. These observed phenotypic changes were accompanied by decreased fibrotic, adipogenic, and atrophy-related gene expression in the injured muscle of mice treated with SB431542. We further demonstrated that treatment with SB431542 reduces the number of fibro/adipogenic progenitor (FAP) cells-an important cellular origin of rotator cuff muscle fibrosis and fatty infiltration, in injured muscle by promoting apoptosis of FAPs. Together, these data indicate that the TGF-ß pathway is a critical regulator of the degenerative muscle changes seen after massive rotator cuff tears. TGF-ß promotes rotator cuff muscle fibrosis and fatty infiltration by preventing FAP apoptosis. TGF-ß regulated FAP apoptosis may serve as an important target pathway in the future development of novel therapeutics to improve muscle outcomes following rotator cuff tear.

Rat rotator cuff muscle responds differently from hindlimb muscle to a combined tendon-nerve injury.

Rotator cuff tears (RCTs) are among the most common musculoskeletal injuries seen by orthopaedic surgeons. Clinically, massive cuff tears lead to unique pathophysiological changes in rotator cuff muscle, including atrophy, and massive fatty infiltration, which are rarely seen in other skeletal muscles. Studies in a rodent model for RCT have demonstrated that these histologic findings are accompanied by activation of the Akt/mammalian target of rapamycin (mTOR) and transforming growth factor-ß (TGF-ß) pathways following combined tendon-nerve injury. The purpose of this study was to compare the histologic and molecular features of rotator cuff muscle and gastrocnemius muscle--a major hindlimb muscle, following combined tendon-nerve injury. Six weeks after injury, the rat gastrocnemius did not exhibit notable fatty infiltration compared to the rotator cuff. Likewise, the adipogenic markers SREBP-1 and PPARγ as well as the TGF-ß canonical pathway were upregulated in the rotator cuff, but not the gastrocnemius. Our study suggests that the rat rotator cuff and hindlimb muscles differ significantly in their response to a combined tendon-nerve injury. Clinically, these findings highlight the unique response of the rotator cuff to injury, and may begin to explain the poor outcomes of massive RCTs compared to other muscle-tendon injuries.

Fetal extraperitoneal rectal perforation: a rare neonatal emergency.

PURPOSE: Intraperitoneal bowel perforation may occur in utero as a result of a variety of abnormalities and typically results in sterile meconium ascites, pseudocysts, and/or calcification in the fetus. On the other hand, extraperitoneal bowel perforation in intrauterine life is extremely rare. The object of this report is to present our experience of prenatal extraperitoneal rectal perforation, defining the clinical presentation, management, and progress. METHODS AND MATERIALS: Nine babies who were identified from 2 centers in the Republic of South Africa with fetal extraperitoneal rectal perforation are presented. The details of these babies were obtained retrospectively from the case notes. RESULTS: All patients presented at or shortly after birth with air and meconium tracking below the pelvic floor manifesting as either an expanding, meconium-stained aerocele or with perirectal spreading sepsis. Where abdominal signs were present, laparotomy confirmed the extension of the meconium perforation into the peritoneal cavity. Management was by diverting colostomy, drainage of the perineal collection, and supportive therapy. A posterior approach to the rectum and excision of a fibrotic section of the lower rectal wall was performed in one case. One case developed rectal stenosis that was treated by dilatation before colostomy closure. In all the other cases, digital examination performed before colostomy closure ruled out significant narrowing. There was no mortality, and the site of the rectal perforation healed in all cases to leave good anorectal function after treatment. CONCLUSIONS: Fetal extraperitoneal perforation is extremely rare, but the clinical features are easily recognizable, and when appropriate therapy is instituted, the outcome is likely to be good with normal anorectal function to be expected in the long-term. The exact cause of the condition is unknown.

Damage control laparotomy for generalized necrotizing enterocolitis.

Macroscopic generalized necrotizing enterocolitis (G-NEC) is associated with a very high mortality in neonates. In some instances, however, multiple bowel segments are necrotic, with most of the remaining small bowel damaged but viable. In these selected patients morbidity can be reduced and survival increased with an aggressive and early surgical approach. We have termed this approach damage control laparotomy (DCL). Over a 5(1/2)-year period, all neonates with G-NEC with adequate length of viable small bowel were subjected to DCL. The procedure is characterized by a resuscitative period of a few hours followed by laparotomy and resection of dead/perforated bowel. The bowel ends are either anastomosed or tied, and the bowel is returned to the abdomen to allow full tissue demarcation. Re-look laparotomy is performed 3-4 days later, at which time any new necrotic bowel is excised and re-joined, to achieve small bowel continuity. In this prospective study, 104 neonates with G-NEC underwent operation; 27 neonates (26%) were considered to have an adequate potential length of viable bowel and were selected for DCL. Nineteen neonates survived in the follow-up period. Early mortality was due to sepsis syndrome in 6 patients, and late mortality in 2 neonates was secondary to the short bowel syndrome. The DCL procedure is another step toward improving survival in surgical G-NEC; this technique avoids proximal stomas and their complications, and at the same time it preserves the best possible bowel length.

Surgical indications and strategies for necrotizing enterocolitis in low income countries.

In high income countries, mortality of neonates due to necrotizing enterocolitis (NEC) is decreasing due to advances in early detection and sepsis management. Surgical strategies, by and large, are becoming less relevant as the sophistication of intensive care facilities increases in those countries. Management of septic neonates with NEC in low income countries, however, due to inherent resource constraints cannot achieve the same standards as those reported from high income countries. Surgeons therefore play an important role because they can offer different surgical strategies in line with the deficiency of their environment. Over a 4-year period, 172 neonates who had surgery for NEC in a single institution were prospectively followed up. Standard surgical practices of the high income countries were compared to those adopted by the authors. The end point was early mortality, taking into account the anatomical zones of the involved intestine. Survival was increased from 21% to 84% by early surgery and by extending the length of colon resected in cases of ileocolic NEC. In this approach, a short resuscitative period is followed by intestinal resection including most of the diseased colon as well as the perforated/dead bowel. A more modest improvement in survival was noted with a planned re-look laparotomy in neonates with generalized NEC.