Age-dependent decline of B3AR agonist-mediated activation of FAP UCP-1 expression in murine models of chronic rotator cuff repair.

Amibegron, a ß3-adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP-1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4-month-old) and aged (33-month-old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6-weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6-weeks post-DR. For in vitro histology and real-time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence-activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8-days after seeding (late exposure). In vitro results showed that amibegron-mediated FAP UCP-1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP-1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP-targeted therapeutics for chronic injuries.

Associations between Body Mass Index, Gait Mechanics and Trochlear Cartilage Thickness in those with ACL Reconstruction.

PURPOSE: High body mass index (BMI) is a strong predictor of post-traumatic osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR). Altered gait mechanics are independently affected by BMI and ACLR, and influence OA risk. Yet, evidence directly assessing the impact of high BMI on gait or cartilage characteristics after ACLR are limited. Here, we evaluated if high BMI moderates associations between gait and trochlear cartilage structure in individuals with ACLR. METHODS: Treadmill walking biomechanics were evaluated in forty normal BMI and twenty-four high BMI participants with ACLR at self-selected speeds. Normalized and absolute peak and cumulative loads (i.e., impulse) were extracted for peak knee flexion and adduction moments (KFM, KAM) and vertical ground reaction force (GRF). Medial and lateral femoral cartilage thickness and medial: lateral thickness ratios were assessed via ultrasound. RESULTS: Those with ACLR and high BMI walked with reduced normalized peak vertical GRFs, and greater absolute peak and cumulative loads compared to normal BMI individuals with ACLR. Those with ACLR and high BMI also exhibited thinner cartilage and greater medial: lateral ratios in ACLR limbs compared to contralateral limbs whereas normal BMI individuals with ACLR exhibited thicker ACLR limb cartilage. Lastly, greater peak KAM and KAM cumulative load were associated with thicker lateral cartilage and lesser medial: lateral thickness ratios, but only in the high BMI group. CONCLUSIONS: We observed those with high BMI after ACLR exhibited trochlear cartilage structural alterations not observed in normal BMI patients, while differential associations between loading outcomes and cartilage thickness in ACLR knees were observed between groups. Those with high BMI after ACLR may require different therapeutic strategies to optimize joint health in this subset of patients.

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.

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.

Biomechanical Effects of Manipulating Preferred Cadence During Treadmill Walking in Patients With ACL Reconstruction.

BACKGROUND: Abnormal gait is common after anterior cruciate ligament reconstruction (ACLR) which may influence osteoarthritis risk in this population. Yet few gait retraining options currently exist in ACLR rehabilitation. Cueing cadence changes is a simple, low-cost method that can alter walking mechanics in healthy adults, but few studies have tested its effectiveness in an ACLR population. Here, we evaluated the acute effects of altering cadence on knee mechanics in patients 9 to 12 months post ACLR. HYPOTHESIS: Cueing larger steps will facilitate larger knee angles and moments, while cueing smaller steps would induce smaller knee angles and moments. STUDY DESIGN: Randomized cross-sectional design. LEVEL OF EVIDENCE: Level 3. METHODS: Twenty-eight patients with unilateral ACLR underwent gait assessments on a treadmill at preferred pace. Preferred walking gait was assessed first to obtain preferred cadence. Participants then completed trials while matching an audible beat set to 90% and 110% of preferred cadence in a randomized order. Three-dimensional sagittal and frontal plane biomechanics were evaluated bilaterally. RESULTS: Compared with preferred cadence, cueing larger steps induced larger peak knee flexion moments (KFMs) and knee extension excursions bilaterally (P < 0.01), whereas cueing smaller steps only reduced knee flexion excursions (P < 0.01). Knee adduction moments remain unchanged across conditions and were similar between limbs (P > 0.05). Peak KFMs and excursions were smaller in the injured compared with uninjured limb (P < 0.01). CONCLUSION: Frontal plane gait outcomes were unchanged across conditions suggesting acute cadence manipulations result in mainly sagittal plane adaptations. Follow-up studies using a longitudinal cadence biofeedback paradigm may be warranted to elucidate the utility of this gait retraining strategy after ACLR. CLINICAL RELEVANCE: Cueing changes in walking cadence can target sagittal plane knee loading and joint range of motion in ACLR participants. This strategy may offer high clinical translatability given it requires relatively minimal equipment (ie, free metronome app) outside of a treadmill.

Cartilage deformation following a walking bout in individuals with anterior cruciate ligament reconstruction.

The purpose was to (1) compare the effect of a walking bout on femoral cartilage deformation between limbs with and without anterior cruciate ligament reconstruction (ACLR) and (2) examine the association between gait kinetics and the magnitude of cartilage deformation. A total of 30 individuals with primary unilateral ACLR completed this study [14 male, 16 female; age = 22.57 (3.78) years; body mass index (BMI) = 25.88 (5.68) kg/m2 ; time since ACLR = 61.00 (16.43) months]. Overground walking biomechanics were assessed on day 1, and a 30-min walking bout or 30-min resting bout (control) were completed on days 2 and 3 (counterbalanced order). Femoral cartilage thickness was measured using ultrasound before, immediately following, and 30-min following each intervention. Linear mixed effects models compared the effect of walking on cartilage thickness between the ACLR and contralateral limbs after adjusting for sex, BMI, speed, and the number of steps. Stepwise regression examined the association between the external knee flexion and adduction moments and cartilage deformation following walking. There was a significant limb × time interaction for medial cartilage thickness. Post hoc analyses indicated that cartilage thickness decreased immediately following walking in the contralateral but not ACLR limb. Main effects of limb were observed for medial, central, and lateral cartilage thickness indicating thicker cartilage in the ACLR compared with contralateral limb. A higher knee adduction moment was associated with greater cartilage deformation in the ACLR limb. Femoral cartilage in the ACLR limb exhibited a less dynamic response to walking than the uninvolved limb, which may be due to habitual underloading during gait.

The Influence of Knee Position on Ultrasound Imaging of Femoral Cartilage in Individuals with Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Articular cartilage is important for knee function and can be imaged using ultrasound. The purpose was to compare femoral cartilage thickness and echo intensity (EI) measured at 90° and 140° of knee flexion and between limbs in a cohort with unilateral anterior cruciate ligament reconstruction (ACLR). We also examined associations between gait biomechanics and cartilage outcomes. METHODS: Twenty-seven individuals with primary unilateral ACLR participated (12 men, 15 women; age = 22.3 ± 3.8 years; time since ACLR = 71.2 ± 47.2 months). Ultrasound was used to obtain femoral cartilage measurements. Gait outcomes included peak KFA (knee flexion angle) and peak external knee flexion moment (KFM). Cartilage outcomes were compared using a 2 (position) × 2 (limb) repeated measures ANOVA (analysis of variance). Gait and cartilage associations were assessed using linear regression. FINDINGS: There were no position × limb interactions for any cartilage outcome (all P > 0.05). Medial (P = 0.038) and central cartilage (P < 0.001) were thicker, whereas central (P = 0.029) and lateral cartilage EI (P = 0.003) were lower when measured at 90° than those at 140° of knee flexion. Medial cartilage was thicker in the ACLR than that in the contralateral limb (P = 0.016). A larger KFM was associated with thicker medial cartilage (ΔR2 = 0.146, P = 0.021) and central cartilage (ΔR2 = 0.159, P = 0.039) measured at 140° of knee flexion in the ACLR limb but not at 90°. INTERPRETATION: Findings suggest that imaging position influences cartilage thickness and EI measurements in individuals with ACLR and should be considered in study designs and clinical evaluation. A greater KFM was associated with thicker cartilage within specific portions of the distal femur.

Walking speed differentially affects lower extremity biomechanics in individuals with anterior cruciate ligament reconstruction compared to uninjured controls.

BACKGROUND: Walking biomechanics are commonly affected after anterior cruciate ligament reconstruction and differ compared to uninjured controls. Manipulating task difficulty has been shown to affect the magnitude of walking impairments in those early after knee surgery but it is unclear if patients in later phases post-op are similarly affected by differing task demands. Here, we evaluated the effects of manipulating walking speed on between-limb differences in ground reaction force and knee biomechanics in those with and without anterior cruciate ligament reconstruction. METHODS: We recruited 28 individuals with anterior cruciate ligament reconstruction and 20 uninjured control participants to undergo walking assessments at three speeds (self-selected, 120%, and 80% self-selected speed). Main outcomes included sagittal plane knee moments, angles, excursions, and ground reaction forces (vertical and anterior-posterior). FINDINGS: We observed walking speed differentially impacted force and knee-outcomes in those with anterior cruciate ligament reconstruction. Between-limb differences increased at fast and decreased at slow speeds in those with anterior cruciate ligament reconstruction while uninjured participants maintained between-limb differences regardless of speed (partial η2 = 0.13-0.33, p < 0.05). Anterior cruciate ligament reconstruction patients underloaded the surgical limb relative to both the contralateral, and uninjured controls in GRFs and sagittal plane knee moments (partial η2 range = 0.13-0.25, p < 0.05). INTERPRETATION: Overall, our findings highlight the persistence of walking impairments in those with anterior cruciate ligament reconstruction despite completing formal rehabilitation. Further research should consider determining if those displaying larger changes in gait asymmetries in response to fast walking also exhibit poorer strength and/or joint health outcomes.

Contributing factors to postural stability in Prader-Willi syndrome.

BACKGROUND: Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder affecting multiple functional parameters. This study examined postural stability and associated gait and neuromuscular factors in young adults with PWS. METHODS: Participants included 10 adults with PWS [7 M/3F; Body Fat % 40.61 ± 7.79]; ten normal weight (NW) adults [7 M/3F; Body Fat % 23.42 ± 7.0]; ten obese (OB) adults [7 M/3F; Body Fat % 42.40 ± 5.62]. Participants completed the Sensory Organization Test (SOT)®. Condition (C) specific and a composite equilibrium score (CES) were calculated (maximum = 100). Quadriceps strength was assessed using an isokinetic dynamometer. Three-dimensional gait analyses were completed along a 10 m walkway using a motion capture system and two force plates. A gait stability ratio (GSR) was computed from gait speed and step length (steps/m). RESULTS: The PWS group had lower scores for C1, C3, C4 and CES compared to the NW (p < .039 for all) and lower scores for C4 and CES than the OB (p < .019 for both) groups, respectively. In C5 (eyes closed, sway-referenced support) and C6 (sway-referenced vision and support), 33.3% of participants with PWS fell during the first trial in both conditions (X2 [2] 7.436, p = .024) and (X2 [2] 7.436, p = .024) but no participant in the other groups fell. Those with PWS showed higher GSR than participants with NW (p = .005) and those with obesity (p = .045). CONCLUSION: Individuals with PWS had more difficulty maintaining standing balance when relying on information from the somatosensory (C3), visual-vestibular (C4) and vestibular systems (C5, C6). A more stable walk was related to shorter steps, slower velocity and reduced peak quadriceps torque. Participation in multisensory activities that require appropriate prioritization of sensory system(s) input for controlling balance in altered sensory environments should be routinely included. In addition, exercises targeting muscular force and power should be included as part of exercise programming in PWS.

Bone mineral density and its relationship with ground reaction force characteristics during gait in young adults with Prader-Willi Syndrome.

Introduction: The incidence of osteopenia and osteoporosis is of concern in adults with Prader-Willi syndrome (PWS). Walking generates reaction forces that could stimulate bone mineralization and is popular in people with PWS. This study compared bone parameters and ground reaction forces (GRF) during gait between young adults with PWS and without PWS and explored associations between bone and GRFs during gait. Methods: 10 adults with PWS, 10 controls with obesity (OB) and 10 with normal weight (NW) matched on sex participated. Segmental and full body dual-energy x-ray absorptiometry scans provided femoral neck, spine, total body minus the head bone mineral density (BMD), bone mineral content (BMC). Vertical GRF, vertical impulse, posterior force and negative impulse were measured during 5 walking trials at a self-selected speed along a 10 m runway. Results: Multivariate analyses of variance showed that adults with PWS (n = 7-8) had hip and body BMD and BMC comparable (p > .050) to NW and lower (p < .050) than OB. Adults with PWS showed slower speed than NW (p < .050) but similar to OB (p > .050). Adults with PWS presented lower absolute vertical GRF, vertical impulse and negative impulse than OB (p < .050). Pearson r correlations (p < .050) in those with PWS (n = 7-8) indicated that femoral neck BMC was associated with vertical GRF (r = 0.716), vertical impulse (r = 0.780), posterior force (r = -0.805), and negative impulse (r = -0.748). Spine BMC was associated with speed (r = 0.829) and body BMD was associated with speed (r = 0.893), and posterior force (r = -0.780). Conclusions: Increased BMC in the femoral neck and body were associated with larger breaking forces during walking, a phenomenon normally observed at greater gait speeds. Faster walking speed was associated with greater BMC in the spine and body. Our preliminary results suggest that young adults with PWS could potentially benefit from faster walking for bone health; however, larger prospective studies are needed to confirm this.

Joint and Limb Loading during Gait in Adults with ACL Reconstruction: Comparison between Single-Step and Cumulative Load Metrics.

PURPOSE: Individuals with anterior cruciate ligament reconstruction (ACLR) generally exhibit limb underloading behaviors during walking, but most research focuses on per-step comparisons. Cumulative loading metrics offer unique insight into joint loading as magnitude, duration, and total steps are considered, but few studies have evaluated if cumulative loads are altered post-ACLR. Here, we evaluated if underloading behaviors are apparent in ACLR limbs when using cumulative load metrics and how load metrics change in response to walking speed modifications. METHODS: Treadmill walking biomechanics were evaluated in 21 participants with ACLR at three speeds (self-selected (SS); 120% SS and 80% SS). Cumulative loads per step and per kilometer were calculated using knee flexion and adduction moment (KFM and KAM) and vertical ground reaction force (GRF) impulses. Traditional magnitude metrics for KFM, KAM, and GRF were also calculated. RESULTS: The ACLR limb displayed smaller KFM and GRF in early and late stances, but larger KFM and GRF during midstance compared with the contralateral limb ( P < 0.01). Only GRF cumulative loads (per step and per kilometer) were reduced in the ACLR limb ( P < 0.01). In response to speed modifications, load magnitudes generally increased with speed. Conversely, cumulative load metrics (per step and per kilometer) decreased at faster speeds and increased at slow speeds ( P < 0.01). CONCLUSIONS: Patients with ACLR underload their knee in the sagittal plane per step, but cumulatively over the course of many steps/distance, this underloading phenomenon was not apparent. Furthermore, cumulative load increased at slower speeds, opposite to what is identified with traditional single-step metrics. Assessing cumulative load metrics may offer additional insight into how load outcomes may be impacted in injured populations or in response to gait modifications.

MDverse: Shedding Light on the Dark Matter of Molecular Dynamics Simulations.

The rise of open science and the absence of a global dedicated data repository for molecular dynamics (MD) simulations has led to the accumulation of MD files in generalist data repositories, constituting the dark matter of MD - data that is technically accessible, but neither indexed, curated, or easily searchable. Leveraging an original search strategy, we found and indexed about 250,000 files and 2,000 datasets from Zenodo, Figshare and Open Science Framework. With a focus on files produced by the Gromacs MD software, we illustrate the potential offered by the mining of publicly available MD data. We identified systems with specific molecular composition and were able to characterize essential parameters of MD simulation, such as temperature and simulation length, and identify model resolution, such as all-atom and coarse-grain. Based on this analysis, we inferred metadata to propose a search engine prototype to explore collected MD data. To continue in this direction, we call on the community to pursue the effort of sharing MD data, and increase populating and standardizing metadata to reuse this valuable matter.

Conserved multi-tissue transcriptomic adaptations to exercise training in humans and mice.

Physical activity is associated with beneficial adaptations in human and rodent metabolism. We studied over 50 complex traits before and after exercise intervention in middle-aged men and a panel of 100 diverse strains of female mice. Candidate gene analyses in three brain regions, muscle, liver, heart, and adipose tissue of mice indicate genetic drivers of clinically relevant traits, including volitional exercise volume, muscle metabolism, adiposity, and hepatic lipids. Although ∼33% of genes differentially expressed in skeletal muscle following the exercise intervention are similar in mice and humans independent of BMI, responsiveness of adipose tissue to exercise-stimulated weight loss appears controlled by species and underlying genotype. We leveraged genetic diversity to generate prediction models of metabolic trait responsiveness to volitional activity offering a framework for advancing personalized exercise prescription. The human and mouse data are publicly available via a user-friendly Web-based application to enhance data mining and hypothesis development.

Indications and Efficacy of Halo-Gravity Traction in Pediatric Spinal Deformity: A Critical Analysis Review.

¼: Halo-gravity traction (HGT) is a well-established technique for correcting severe spinal deformity in pediatric patients. ¼: HGT induces soft-tissue relaxation and gradually lengthens the spine, and it can be used preoperatively and intraoperatively. ¼: It is typically indicated for spinal deformity over 90° in any plane and medical optimization. ¼: There are several complications associated with the use of HGT, and it is critical to follow a protocol and perform serial examinations to minimize this risk.

Dynamic knee stiffness during walking is increased in individuals with anterior cruciate ligament reconstruction.

Individuals with anterior cruciate ligament (ACL) reconstruction often display abnormal gait mechanics reflective of a "stiff-knee" gait (i.e., reduced knee flexion angles and moments). However, dynamic knee stiffness, which is the dynamic relationship between the position of the knee and the moment acting on it, has not been directly examined during walking in individuals with ACL reconstruction. Here, we aimed to evaluate dynamic knee stiffness in the involved compared to the uninvolved limb during weight-acceptance and mid-stance phases of walking. Twenty-six individuals who underwent ACL reconstruction (Age: 20.2 ± 5.1 yrs., Time post-op: 7.2 ± 0.9 mo.) completed an overground walking assessment using a three-dimensional motion capture system and two force plates. Dynamic knee stiffness (Nm/°) was calculated as the slope of the regression line during weight-acceptance and midstance, obtained by plotting the sagittal plane knee angle versus knee moment. Paired t-tests with Bonferroni corrections were used to compare differences in dynamic stiffness, knee excursions, and moment ranges between limbs during both stance phases. Greater dynamic knee stiffness was found in the involved compared with the uninvolved limb during weight-acceptance and mid-stance (p < 0.01). Knee flexion and extension excursions were reduced in the involved limb during both weight-acceptance and mid-stance, respectively (p < 0.01). Sagittal plane knee moment ranges were not different between limbs during weight-acceptance (p = 0.1); however, the involved limb moment range was reduced relative to the uninvolved limb during mid-stance (p < 0.01). These results indicate that individuals with ACL reconstruction walk with a stiffer knee throughout stance, which may influence knee contact forces and could contribute to the high propensity for post-traumatic knee osteoarthritis development in this population.

Influence of body mass index and anterior cruciate ligament reconstruction on gait biomechanics.

Body mass index (BMI) and history of anterior cruciate ligament reconstruction (ACLR) independently influence gait biomechanics and knee osteoarthritis risk, but the interaction between these factors is unclear. The purpose of this study was to compare gait biomechanics between individuals with and without ACLR, and with and without overweight/obesity. We examined 104 individuals divided into four groups: with and without ACLR, and with low or high BMI (n = 26 per group). Three-dimensional gait biomechanics were evaluated at preferred speed. The peak vertical ground reaction force, knee flexion angle and excursion, external knee flexion moment, and external knee adduction moment were extracted for analysis. Gait features were compared between groups using 2 (with and without overweight/obesity) × 2 (with and without ACLR) analysis of variance. Primary findings indicated that those with ACLR and high BMI had a larger external knee adduction moment compared with those with low BMI and with (p = 0.004) and without ACLR (p = 0.005), and compared with those without ACLR and high BMI (p = 0.001). The main effects of ACLR and BMI group were found for the knee flexion moment, and those with ACLR and with high BMI had lower knee flexion moments compared with those without ACLR (p = 0.031) and with low BMI (p = 0.021), respectively. Data suggest that individuals with ACLR and high BMI may benefit from additional intervention targeting the knee adduction moment. Moreover, lower external knee flexion moments in those with high BMI and ACLR were consistent, but high BMI did not exacerbate deficits in the knee flexion moment in those with ACLR. [Correction added on 9 November 2022, after first online publication: In the preceding sentence, for clarity, the words "reductions in the lower" was removed from the initial sentence to read "Moreover, lower external knee flexion moments".].

Electrically Evoked Torque at Rest is Strongly Related to Quadriceps Muscle Size in Individuals with Anterior Cruciate Ligament Reconstruction.

Electrically evoked torque at rest (i.e., the torque produced from supramaximal stimul applied to a resting muscle) has been shown to be related to muscle size in healthy adults, but this relationship has not been evaluated in pathological populations where atrophy is present. This study aimed to evaluate the relationship between the electrically evoked torque at rest and vastus lateralis cross-sectional area (CSA) in individuals with anterior cruciate ligament (ACL) reconstruction. Eighteen individuals with ACL reconstruction participated. Quadriceps electrically evoked torque at rest was elicited bilaterally via sex-specific, standardized supramaximal triplet stimulations. Vastus lateralis CSA was measured at 50% of thigh length using ultrasound. Pearson's r and partial correlations were used to evaluate associations between outcomes. Evoked torque at rest was positively associated with vastus lateralis CSA in the ACL reconstructed limb (r=0.865, partial r=0.816, P<0.01), non-reconstructed limb (r=0.628, partial r=0.575, P<0.05), and side-to-side ratios (r=0.670, partial r=0.659, P<0.01). These results indicate that electrically evoked torque at rest may indirectly assess side-to-side differences in quadriceps muscle size after ACL reconstruction.

Lower extremity coordination and joint kinetic distribution during gait in adults with and without Prader-Willi Syndrome.

Individuals with Prader-Willi Syndrome (PWS) have reduced mobility, which may be due to altered gait biomechanics. This study compared lower extremity intersegmental coordination and joint kinetics in adults with and without PWS. Walking biomechanics were evaluated in 10 adults with PWS and 10 controls without and 10 with obesity. The foot-shank and shank-thigh coordination was evaluated using modified vector coding and compared between groups using Kruskal-Wallis and Mann-Whitney U tests. The total support moment was summed from the ankle, knee, and hip extensor moments; and relative joint contributions were expressed as a percentage and compared between groups using one-way MANOVA. The group with PWS had greater exclusive shank segment rotation during later stance compared with controls with (p < 0.001) and without obesity (p < 0.001). The group with PWS also had a smaller absolute total support moment than controls with obesity during early and late stance (both p < 0.001), and lower normalized total support moment compared to controls without obesity during early stance (p = 0.019) and compared to controls with obesity during late stance (p = 0.004). Extensor moment contributions was similar between groups during early and late stance (all p > 0.05). Findings suggest a flat-footed gait pattern in PWS during late stance, which may negatively influence propulsion and speed. Moreover, those with PWS had lower total support moments than controls during early and late stance, but similar relative extensor contributions when walking at self-selected speeds. As such, improving overall torque generation in the lower extremity may be useful to improve stability and mobility during gait in PWS.

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.

Developmental Dysplasia of the Hip: Controversies in Management.

PURPOSE OF REVIEW: Many aspects of developmental hip dysplasia (DDH) care and evaluation are still active areas of debate. Recent studies have provided more insight into these topics such as strategies for reducing osteonecrosis, assessing hip reduction after closed and open reduction, and the management of residual acetabular dysplasia. RECENT FINDINGS: The presence of the ossific nucleus at the time of reduction does not alter the risk of osteonecrosis. The risk of osteonecrosis may be higher when hips are immobilized in excessive abduction. Limited sequence MRI may be the best choice for assessing hip reduction after closed and open reduction; however, new technologies are emerging such as 3D fluoroscopy and perfusion MRI. The treatment of residual acetabular dysplasia with bracing has been shown to be effective and the decision to perform a pelvic osteotomy is based on patient-specific factors. The spectrum of DDH treatment has evolved over the past several decades. Recent studies have provided insights into strategies for osteonecrosis prevention, hip evaluation during after reduction, and the management of residual acetabular dysplasia. However, there is ample room for additional and more rigorous studies guiding advanced imaging for assessing hip reduction such as 3D fluoroscopy and perfusion MRI, as well as the management of residual acetabular dysplasia.