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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]

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]

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 β-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 β-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 β-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 β-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 β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Biomechanical knee asymmetry is commonly present after anterior cruciate ligament (ACL) reconstruction. Factors that could assist in identification of asymmetrical biomechanics after ACL reconstruction could help clinicians in making return-to-play decisions. The purpose of this study is to determine factors that may contribute to knee biomechanical asymmetry present after ACL reconstruction. Hypothesis: We hypothesized that quadriceps strength and activation and patient-reported function would allow for identification of patients with symmetrical knee biomechanics. Study Design: Cross-sectional study. Level of Evidence: Level 3. Methods: Thirty-one subjects (18 women; time since ACL reconstruction = 284.4 ± 53.6 days) who underwent ACL reconstruction and were to return to activity were recruited. Participants completed bilateral assessments of isokinetic quadriceps strength, quadriceps activation using the superimposed burst technique, and biomechanical function testing during a single-leg forward hop. The International Knee Documentation Committee (IKDC) subjective knee form was also completed. Symmetry values were calculated for each variable. Decision trees were utilized to determine which input factors (quadriceps strength symmetry, quadriceps activation symmetry, IKDC score, age, sex, height, mass, graft type) were able to identify participants who had symmetrical knee flexion angles (KFAs) and extension moments. Angles and moments were considered symmetrical if symmetry values were ≥90%. Results: Quadriceps strength and activation symmetry were able to predict whether a patient landed with symmetrical or asymmetrical KFAs, with thresholds of 77.2% strength symmetry and 91.3% activation symmetry being established. Patient-reported function and quadriceps strength were factors that allowed for classification of participants with symmetrical/asymmetrical knee extension moments, with thresholds of 89.1 for the IKDC and 80.0% for quadriceps strength symmetry. Conclusions: Quadriceps strength contributed to both models and appears to be a critical factor for achieving symmetrical knee biomechanics. High patient-reported function and quadriceps activation are also important for restoring knee biomechanical symmetry after ACL reconstruction. Clinical Relevance: Quadriceps strength and activation and patient-reported function may be able to assist clinicians in identifying ACL patients with symmetrical/asymmetrical knee biomechanics. [ABSTRACT FROM AUTHOR]

Background: Reductions in muscle size are common after anterior cruciate ligament reconstruction (ACLR) and may contribute to suboptimal patient outcomes. However, few studies have quantified postoperative alterations in muscle quality and evaluated its associations with patient-reported function.Hypotheses: Rectus femoris cross-sectional area (CSA) will decrease postoperatively but improve at return to activity (RTA), rectus femoris muscle quality (percentage fat [PF]) will increase postoperatively and be greater at RTA compared with preoperative values, and rectus femoris CSA and PF will be associated with International Knee Documentation Committee (IKDC) scores at both postoperative time points.Study Design: Case series.Level Of Evidence: Level 4.Methods: A total of 26 individuals who sustained an ACL injury and underwent reconstructive surgery were evaluated preoperatively (T0), 9 weeks post-ACLR (T1), and at RTA. Rectus femoris CSA and PF were evaluated bilaterally via ultrasound imaging, and patient-reported function was assessed using the IKDC score.Results: Bilateral reductions in rectus femoris CSA were noted from T0 to T1 (P < 0.01). Only the uninvolved limb returned to preoperative CSA (P = 0.80), as the involved limb failed to return to preoperative levels at RTA (P = 0.04). No significant changes in rectus femoris PF were observed across time points (P > 0.05). Lesser PF (P < 0.01) but not CSA (P = 0.75) was associated with higher IKDC score at T1. Lesser PF (P = 0.04) and greater CSA (P = 0.05) was associated with higher IKDC score at RTA.Conclusion: Substantial atrophy occurs bilaterally after ACLR, and the involved limb does not return to preoperative muscle size despite the patient completing rehabilitation. Quadriceps muscle morphology is associated with patient-reported function and may be an important rehabilitation target after ACLR.Clinical Relevance: Quadriceps atrophy and poor muscle quality may contribute to suboptimal patient functioning and quadriceps dysfunction and may be important in RTA decision making. Assessing muscle morphology using ultrasound may be a feasible and clinically beneficial tool in patients after ACLR. [ABSTRACT FROM AUTHOR]