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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.

Purpose of reviewMany 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 findingsThe 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.

PURPOSE OF REVIEW:With an increase in high-demand sporting activity, the rate of pediatric and adolescent anterior cruciate ligament (ACL) reconstruction is increasing. Yet, the failure rates after reconstruction are much higher than the adult population. The purpose of this paper is to understand failure rates, reasons for graft failure, and strategies for successful revision surgery. RECENT FINDINGS:A complete understanding of the failure etiology is essential for the clinician treating this population prior to revision. This begins with an assessment of post-operative patient compliance and sporting activity. Surgical technique must then be scrutinized for non-anatomic tunnel placement and poor graft size/type. Concurrent bony deformity must also be addressed including lower extremity valgus alignment and tibial slope abnormalities. Meniscus and chondral injury must be aggressively treated. Furthermore, imaging must be examined to look for missed posterolateral corner injury. Lateral extra-articular tenodesis (in the setting of ligamentous laxity or rotational instability) may be also indicated as well. The surgeon can then choose a graft type and surgical technique that optimizes outcome and respects skeletal growth. Prior to surgical intervention, the clinician must also counsel patients in regard to the guarded prognosis and outcomes in this setting. Prolonged rehabilitation protocols/return-to-play timing as well as sporting activity modification in the post-operative period after revision are critical. There is limited literature on revision ACL reconstruction in the skeletally immature athlete. An understanding of all the risk factors for failure is essential in order to achieve treatment success.

Although heterogeneity is recognized within the murine satellite cell pool, a comprehensive understanding of distinct subpopulations and their functional relevance in human satellite cells is lacking. We used a combination of single cell RNA sequencing and flow cytometry to identify, distinguish, and physically separate novel subpopulations of human PAX7+ satellite cells (Hu-MuSCs) from normal muscles. We found that, although relatively homogeneous compared to activated satellite cells and committed progenitors, the Hu-MuSC pool contains clusters of transcriptionally distinct cells with consistency across human individuals. New surface marker combinations were enriched in transcriptional subclusters, including a subpopulation of Hu-MuSCs marked by CXCR4/CD29/CD56/CAV1 (CAV1+). In vitro, CAV1+ Hu-MuSCs are morphologically distinct, and characterized by resistance to activation compared to CAV1- Hu-MuSCs. In vivo, CAV1+ Hu-MuSCs demonstrated increased engraftment after transplantation. Our findings provide a comprehensive transcriptional view of normal Hu-MuSCs and describe new heterogeneity, enabling separation of functionally distinct human satellite cell subpopulations.

Electrically evoked torque at rest (i.e., the torque produced from supramaximal stimuli 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 aims 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.

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.

Investigation of human muscle regeneration requires robust methods to purify and transplant muscle stem and progenitor cells that collectively constitute the human satellite cell (HuSC) pool. Existing approaches have yet to make HuSCs widely accessible for researchers, and as a result human muscle stem cell research has advanced slowly. Here, we describe a robust and predictable HuSC purification process that is effective for each human skeletal muscle tested and the development of storage protocols and transplantation models in dystrophin-deficient and wild-type recipients. Enzymatic digestion, magnetic column depletion, and 6-marker flow-cytometric purification enable separation of 104 highly enriched HuSCs per gram of muscle. Cryostorage of HuSCs preserves viability, phenotype, and transplantation potential. Development of enhanced and species-specific transplantation protocols enabled serial HuSC xenotransplantation and recovery. These protocols and models provide an accessible system for basic and translational investigation and clinical development of HuSCs.

Background: Both high body mass index (BMI) and anterior cruciate ligament reconstruction (ACLR) independently influence knee osteoarthritis risk. Preliminary evidence shows the combination of these risk factors leads to poorer recovery and altered biomechanical outcomes after ACLR, but few studies have directly evaluated early changes in cartilage health between normal-BMI and high-BMI groups in this population. Purpose: To evaluate ultrasound-based measures of cartilage strain and compositional changes (via echo-intensity [EI]) in response to an incline walking stress test between normal-BMI and high-BMI individuals with ACLR. A secondary evaluation was conducted of associations between habitual walking biomechanics (ie, ground-reaction forces, sagittal knee kinetics and kinematics) and cartilage strain and EI outcomes. Study Design: Controlled laboratory study. Methods: Gait biomechanics and femoral trochlear ultrasound analyses were evaluated in 64 participants with ACLR who had normal BMI (BMI < 27.0; n = 40) and high BMI (BMI ≥ 27.0; n = 24). Ultrasound images were collected bilaterally before and after an incline treadmill walk, and medial and lateral trochlear strain and EI changes pre-post exercise were used to compare BMI groups and limbs. Gait outcomes included ground-reaction forces, peak sagittal plane knee moments, angles, and excursions and were used to determine associations with cartilage outcomes in the entire cohort. Results: High-BMI individuals with ACLR exhibited greater medial trochlear cartilage strain in the ACLR limb compared with normal-BMI individuals (approximately 6%; P <.01). In those with high BMI, the ACLR limb exhibited greater medial trochlear strain relative to non-ACLR limbs (approximately 4%; P <.05), but between-limb differences were not observed in the normal-BMI group (P >.05). Medial trochlear EI changes were greater bilaterally in those with high BMI compared with normal-BMI ACLR counterparts (approximately 10%; P <.01). Last, individuals who walked with greater peak knee flexion angles exhibited less medial cartilage strain (Δ R 2 = 0.06; P =.025). Conclusion: The data suggested that high BMI affects cartilage functional properties after ACLR, whereas smaller knee flexion angles were associated with larger medial cartilage strain. Clinical Relevance: High-BMI individuals with ACLR may represent a subset of patients exhibiting earlier declines in cartilage functional integrity in response to loading, necessitating additional or more targeted interventions to mitigate disease development. [ABSTRACT FROM AUTHOR]

Amibegron, a β3‐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. [ABSTRACT FROM AUTHOR]

Purpose: High body mass index (BMI) is a strong predictor of posttraumatic 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 40 normal BMI and 24 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 with normal BMI individuals with ACLR. Those with ACLR and high BMI also exhibited thinner cartilage and greater medial/lateral ratios in ACLR limbs compared with contralateral limbs whereas norma lBMI 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, whereas 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]