Search

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.

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]

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]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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".] [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]