Publications by authors named "Michael Kjaer"

282 Publications

Right-left asymmetry in corticospinal tract microstructure and dexterity are uncoupled in late adulthood.

Neuroimage 2021 Jul 16;240:118405. Epub 2021 Jul 16.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital - Amager and Hvidovre, Kettegård Allé 30, 2650 Hvidovre, Denmark; Faculty of Health and Medical Sciences, Institute for Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark; Department of Neurology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, 2400 København NV, Denmark.

Ageing leads to a decline in white matter microstructure and dexterous function of the hand. In adolescents, it has previously been shown that the degree of right-left asymmetry in the corticospinal tract (CST) is linearly related with right-left asymmetry in dexterity. Here, we tested whether this association is also expressed in older adults. Participants completed a simple circle drawing task with their right and left hand as a measure of dexterity and underwent whole-brain diffusion weighted imaging at 3 Tesla (n = 199; aged 60-72 years). Fractional anisotropy and mean diffusivity of right and left CST were extracted from a manually defined region-of-interest. Linear regression analyses were computed to replicate the analyses in adolescents. Frequentist analyses were complemented with a Bayesian analytical framework. Outcome measures were compared with those previously reported in adolescents (aged 11-16 years). Asymmetries in white matter microstructure of the CST were evident and comparable to the degree of lateralisation observed in adolescence. Similarly, asymmetries in dexterity were evident, but to a lesser degree than in adolescents. Unlike in adolescents, we found no evidence of a linear relationship between asymmetries in CST microstructure and dexterity. Complementary Bayesian regression analysis provided moderate evidence in favour of the null hypothesis, pointing towards a lack of association between the structural and functional measures of right-left asymmetry. Our findings are compatible with the notion that, by late adulthood, a diverging impact of age on white matter structure and dexterous hand function dilutes the structure-function relationship between CST microstructure and manual proficiency that has been reported in adolescents.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118405DOI Listing
July 2021

Chronic Sequelae After Muscle Strain Injuries: Influence of Heavy Resistance Training on Functional and Structural Characteristics in a Randomized Controlled Trial.

Am J Sports Med 2021 Jul 15:3635465211026623. Epub 2021 Jul 15.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital-Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Background: Muscle strain injury leads to a high risk of recurrent injury in sports and can cause long-term symptoms such as weakness and pain. Scar tissue formation after strain injuries has been described, yet what ultrastructural changes might occur in the chronic phase of this injury have not. It is also unknown if persistent symptoms and morphological abnormalities of the tissue can be mitigated by strength training.

Purpose: To investigate if heavy resistance training improves symptoms and structural abnormalities after strain injuries.

Study Design: Randomized controlled trial; Level of evidence, 1.

Methods: A total of 30 participants with long-term weakness and/or pain after a strain injury of the thigh or calf muscles were randomized to eccentric heavy resistance training of the injured region or control exercises of the back and abdominal muscle. Isokinetic (hamstring) or isometric (calf) muscle strength was determined, muscle cross-sectional area measured, and pain and function evaluated. Scar tissue ultrastructure was determined from biopsy specimens taken from the injured area before and after the training intervention.

Results: Heavy resistance training over 3 months improved pain and function, normalized muscle strength deficits, and increased muscle cross-sectional area in the previously injured region. No systematic effect of training was found upon pathologic infiltration of fat and blood vessels into the previously injured area. Control exercises had no effect on strength, cross-sectional area, or scar tissue but a positive effect on patient-related outcome measures, such as pain and functional scores.

Conclusion: Short-term strength training can improve sequelae symptoms and optimize muscle function even many years after a strain injury, but it does not seem to influence the overall structural abnormalities of the area with scar tissue.

Registration: NCT02152098 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/03635465211026623DOI Listing
July 2021

RNA-sequencing and immunofluorescence of the myotendinous junction of mature horses and humans.

Am J Physiol Cell Physiol 2021 Jul 14. Epub 2021 Jul 14.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.

The myotendinous junction (MTJ) is a specialised interface for transmitting high forces between muscle and tendon and yet the MTJ is a common site of strain injury with a high recurrence rate. The aim of this study was to identify previously unknown MTJ components in mature animals and humans. Samples were obtained from the superficial digital flexor (SDF) muscle-tendon interface of 20 horses and the tissue was separated through a sequential cryo-sectioning approach into muscle, MTJ (muscle tissue enriched in myofiber tips attached to the tendon), and tendon fractions. RT-PCR was performed for genes known to be expressed in the three tissue fractions and t-SNE plots were used to select the muscle, MTJ and tendon samples from 5 horses for RNA-sequencing. The expression of previously known and unknown genes identified through RNA-sequencing was studied by immunofluorescence on human hamstring MTJ tissue. The main finding was that RNA-sequencing identified expression of a panel of 61 genes enriched at the MTJ. 48 of these genes were novel for the MTJ, and 13 genes had been reported to be associated with the MTJ in earlier studies. The expression of known (COL22A1, NCAM, POSTN, NES, OSTN) and previously undescribed (MNS1 and LCT) MTJ genes was confirmed at the protein level by immunofluorescence on tissue sections of human MTJ. In conclusion, in muscle-tendon interface tissue enriched with myofiber tips, we identified expression of previously unknown MTJ genes representing diverse biological processes, which may be important in the maintenance of the specialized MTJ.
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http://dx.doi.org/10.1152/ajpcell.00218.2021DOI Listing
July 2021

Mechanical properties and UTE-T2* in Patellar tendinopathy: The effect of load magnitude in exercise-based treatment.

Scand J Med Sci Sports 2021 Jun 30. Epub 2021 Jun 30.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen Denmark and Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Denmark.

Loading intervention is currently the preferred management of tendinopathy, but to what extent different loading regimes influence the mechanical response in tendons is scarcely investigated. Therefore, the purposes of the investigation were to examine the effect of exercise interventions with either high or low load magnitude applied to the tendinopathic patellar tendon and the influence on its mechanical, material, and morphological properties. Forty-four men with chronic patellar tendinopathy were randomized to 12 weeks of exercising with either; 55% of 1RM throughout the period (MSR group) or 90% of 1RM (HSR group), and with equal total exercise volume in both groups. Mechanical (stiffness), material (T2* relaxation time), and morphological (cross-sectional area (CSA)) properties were assessed at baseline and after 12 weeks of intervention. MRI with ultra-short echo times (UTE) and T2*-mapping was applied to explore if T2* relaxation time could be used as a noninvasive marker for internal material alteration and early change thereof in response to intervention. There was no effect of HSR or MSR on the mechanical (stiffness), material (T2* relaxation time) or morphological (CSA) properties, but both regimes resulted in significant strength gain. In conclusion, there were no statistically superior effect of exercising with high (90%) compared to moderate (55%) load magnitude on the mechanical, material or morphological properties.
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http://dx.doi.org/10.1111/sms.14013DOI Listing
June 2021

No Treatment Benefits of Local Administration of Insulin-like Growth Factor-1 in Addition to Heavy Slow Resistance Training in Tendinopathic Human Patellar Tendons: A Randomized, Double-Blind, Placebo-Controlled Trial With 1-Year Follow-up.

Am J Sports Med 2021 Jul 17;49(9):2361-2370. Epub 2021 Jun 17.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M81, Bispebjerg Hospital, Copenhagen, Denmark.

Background: Heavy slow resistance (HSR) training is currently recommended as part of the treatment of patellar tendon tendinopathy. However, treatment success is not reached in all patients, and combinations of different treatments could be beneficial. Local administration of insulin-like growth factor-1 (IGF-1) in humans has been shown to quickly stimulate tendon collagen synthesis.

Purpose: To study whether IGF-1 injections combined with HSR training enhance tendon synthesis, tissue structure, and patient satisfaction versus saline injection combined with HSR training in patients with patellar tendinopathy.

Study Design: Randomized controlled trial; Level of evidence, 1.

Methods: Forty patients (age 18-50 years) with unilateral patellar tendinopathy undertook HSR training (3 times a week for 12 weeks) and received intratendinous IGF-1 injections (1 mg IGF-1 per dose) or isotonic saline injections (sham injections) at baseline and after 1 and 2 weeks of training. The primary outcome was collagen synthesis parameters after 12 weeks (primary endpoint). The secondary outcomes were patient-reported outcomes (scores on the Victorian Institute of Sport Assessment-Patella [VISA-P] and visual analog scale [VAS] for pain) and structural changes before the initiation of treatment and at week 3, week 12, and 1 year after the initiation of treatment.

Results: Analysis of the patellar tendon biopsy specimens at 12 weeks showed that collagen mRNA and total RNA were increased in the tendinopathic tendons compared with the contralateral healthy tendons regardless of treatment with IGF-1 or saline. Similarly, no difference between the groups was seen in tendon thickness and Doppler activity at week 12 or at 1-year follow-up. The combination of HSR training and IGF-1 injections significantly improved VISA-P and VAS pain scores after 3 weeks, whereas the overall responses after 12 weeks and at 1-year follow-up were identical in the 2 groups.

Conclusion: Although a small, immediate clinical response to IGF-1 injections was seen when combined with training, no additional long-term effect of intratendinous IGF-1 was observed on structural and clinical outcomes in patients with patellar tendinopathy.

Registration: NCT01834989 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/03635465211021056DOI Listing
July 2021

Nampt controls skeletal muscle development by maintaining Ca homeostasis and mitochondrial integrity.

Mol Metab 2021 Jun 11;53:101271. Epub 2021 Jun 11.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Objective: NAD is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD synthesis, and in skeletal muscle, NAD is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD biosynthesis in skeletal muscle development and function.

Methods: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates.

Results: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival.

Conclusions: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca homeostasis and skeletal muscle development, which is vital for juvenile survival.
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http://dx.doi.org/10.1016/j.molmet.2021.101271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259345PMC
June 2021

Chronic hyperglycemia, hypercholesterolemia, and metabolic syndrome are associated with risk of tendon injury.

Scand J Med Sci Sports 2021 May 8. Epub 2021 May 8.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Copenhagen University Hospital - Bispebjerg and Frederiksberg and Center for Healthy Aging, Institute of Sports Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark.

Tendon injury is a considerable problem affecting both physically active and sedentary people. The aim of this study was to examine the relationship between markers for metabolic disorders (hyperglycemia, hypercholesterolemia, and metabolic syndrome) and the risk of developing tendon injuries requiring referral to a hospital. The Copenhagen City Heart Study is a prospective study of diabetic and non-diabetic individuals from the Danish general population with different physical activity levels. The cohort was followed for 3 years via national registers with respect to tendon injuries. Data from 5856 individuals (median age 62 years) were included. The overall incidence of tendon injury in both upper and lower extremities that required an out-patient or in-house visit to a hospital was ~5.7/1000 person years. Individuals with elevated HbA1c (glycated hemoglobin) even in the prediabetic range (HbA1c>5.7%) had a ~3 times higher risk of tendon injury in the lower extremities only, as compared to individuals with normal HbA1C levels. Hypercholesterolemia (total cholesterol>5 mmol/L) increased risk of tendon injury in the upper extremities by ~1.5 times, and individuals with metabolic syndrome had ~2.5 times higher risk of tendon injury in both upper and lower extremities. In conclusion, these data demonstrate for the first time in a large cohort with different physical activity levels that the indicators for metabolic syndrome are a powerful systemic determinant of tendon injury, and two of its components, hyperglycemia and hypercholesterolemia, each independently make tendons susceptible for damage and injury.
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http://dx.doi.org/10.1111/sms.13984DOI Listing
May 2021

Exercise in patients with hip osteoarthritis - effects on muscle and functional performance: A randomized trial.

Physiother Theory Pract 2021 May 6:1-12. Epub 2021 May 6.

Department of Physical and Occupational Therapy, Copenhagen University Hospital - Bispebjerg Frederiksberg, Copenhagen NV, Denmark.

: It is believed that clinical management of osteoarthritis should address muscle weakness to improve physical function and prevent disability and frailty.: This sub-study investigated the effects of supervised progressive resistance training (RT), supervised Nordic Walking (NW), and unsupervised home-based exercise (HBE) on muscle and functional performance; and associations between these exercise-induced changes in persons with hip osteoarthritis.: Forty-two patients with hip osteoarthritis were recruited from a larger RCT (NCT01387867). All the groups (RT, = 15; NW, = 12; HBE, = 15) exercised 1 h 3 times/week for 4 months. Quadriceps cross-sectional area (QCSA, MRI-determined); quadriceps strength (QMVC); leg extensor power (LEP); functional performance (chair stands (30sCS); stair climbs (TSC); and 6-minute walk (6MWT)) were assessed at baseline and 4 months.: Per protocol analyses (one-way ANOVA and Bonferroni test) showed significant between-group differences for improvements in QCSA in the most symptomatic leg favoring RT versus NW (2.3 cm, 95% CI [0.6, 3.9]) and HBE (2.3 cm [0.8, 3.9]); and 30sCS (1.8 repetitions [0.2-3.3]), and 6MWT (35.1 m [3.5-66.7]) favoring NW versus HBE. Associations existed between exercise-induced changes in QCSA and QMVC ( = 0.366, = .019) for the most symptomatic leg and between changes in 6MWT and QMVC ( = 0.320, = .04) and LEP ( = 0.381, = .01), respectively, for the least symptomatic leg.: Resistance training appeared effective for improving muscle mass, but less effective for improving muscle strength, power, and functional performance. Only exercise-induced changes in muscle strength and power of the least symptomatic leg, not the most symptomatic leg, were related to changes in functional performance.
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http://dx.doi.org/10.1080/09593985.2021.1923096DOI Listing
May 2021

Resting in bed - how quickly does the muscle lose its nerve?

J Physiol 2021 06 11;599(12):2995-2996. Epub 2021 May 11.

Department of Orthopedic Surgery, Institute of Sports Medicine Copenhagen, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.

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http://dx.doi.org/10.1113/JP281761DOI Listing
June 2021

No Additive Clinical or Physiological Effects of Short-term Anti-inflammatory Treatment to Physical Rehabilitation in the Early Phase of Human Achilles Tendinopathy: A Randomized Controlled Trial.

Am J Sports Med 2021 06 15;49(7):1711-1720. Epub 2021 Mar 15.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of Achilles tendinopathy, but whether they have any additive clinical effect on physical rehabilitation in the early phase of tendinopathy remains unknown.

Purpose/hypothesis: To investigate whether an initial short-term NSAID treatment added to a physical rehabilitation program in the early phase of Achilles tendinopathy would have an additive effect. We hypothesized that the combination of NSAID and rehabilitation would be superior to rehabilitation alone.

Study Design: Randomized controlled trial; Level of evidence, 1.

Methods: A total of 69 patients with early phase Achilles tendinopathy (lasting <3 months) were randomly assigned to either a naproxen group (7 days of treatment; 500 mg twice daily; n = 34) or a placebo group (7 days of placebo treatment; n = 35). Both groups received an identical 12-week physical rehabilitation program. The clinical outcome of the study was evaluated using the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire and a numerical rating scale (NRS), and the physiological outcome was evaluated using ultrasonography, magnetic resonance imaging (MRI), and ultra-short time to echo T2* mapping MRI (UTE T2* MRI). Follow-up was performed at 1 week, 3 months, and 1 year. Time effects are presented as mean difference ± SEM.

Results: No significant differences were found between the 2 treatment groups for any of the outcome measures at any time point ( > .05). For the VISA-A score, a significant time effect was observed between baseline and 3-month follow-up (14.9 ± 2.3; < .0001), and at 1-year follow-up, additional improvements were observed (6.1 ± 2.3; < .01). Furthermore, the change in VISA-A score between baseline and 3-month follow-up was greater in patients with very short symptom duration (<1 month) at baseline compared with patients who had longer symptom duration (>2 months) (interaction between groups, 11.7 ± 4.2; < .01). Despite clinical improvements, total weekly physical activity remained lower compared with preinjury levels at 3 months (-2.7 ± 0.5 h/wk; < .0001) and 1 year (-3.0 ± 0.5 h/wk; < .0001). At baseline, ultrasonography showed increased thickness (0.12 ± 0.03 cm; < .0001) and vascularity (0.3 ± 0.1 cm; < .005) on the tendinopathic side compared with the contralateral side, but no changes over time were observed for ultrasonography, MRI, or UTE T2* MRI results.

Conclusion: Clinical symptoms in early tendinopathy improved with physical rehabilitation, but this improvement was not augmented with the addition of NSAID treatment. Furthermore, this clinical recovery occurred in the absence of any measurable structural alterations. Finally, clinical improvements after a physical rehabilitation program were greater in patients with very short symptom duration compared with patients who had longer symptom duration.

Registration: NCT03401177 (ClinicalTrials.gov identifier) and BFH-2016-019 (Danish Data Protection Agency).
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http://dx.doi.org/10.1177/0363546521991903DOI Listing
June 2021

Magnetic Resonance T * Is Increased in Patients With Early-Stage Achilles and Patellar Tendinopathy.

J Magn Reson Imaging 2021 Mar 14. Epub 2021 Mar 14.

Department of Orthopedic Surgery, Institute of Sports Medicine Copenhagen, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.

Background: T * mapping has proven useful in tendon research and may have the ability to detect subtle changes at an early stage of tendinopathy.

Purpose: To investigate the difference in T * between patients with early tendinopathy and healthy controls, and to investigate the relationship between T * and clinical outcomes, tendon size, and mechanical properties.

Study Type: Prospective cross-sectional.

Subjects: Sixty-five patients with early tendinopathy and 25 healthy controls.

Field Strength/sequence: Three Tesla, ultrashort time to echo magnetic resonance imaging.

Assessment: Tendon T * was quantified using a monoexponential fitting algorithm. Clinical symptoms were evaluated using the Victorian Institute of Sports Assessment-Achilles/Patella (VISA-A/VISA-P). In vivo mechanical properties were measured using an ultrasound-based method that determined force and deformation simultaneously in tendons of patellar tendinopathy patients.

Statistical Tests: A generalized linear model adjusted for age was applied to investigate the difference between patients and controls. In the two patient groups, linear regressions were applied to investigate the association between T * and tendon size, clinical outcomes, and biomechanical properties.

Results: There was a significant difference in T * between patients and healthy controls (204.8 [95% CI: 44.5-365.0] μsec, P < 0.05). There was a positive correlation between tendon size and T * for both Achilles (r = 0.72; P < 0.05) and patellar tendons (r = 0.53; P < 0.05). There was no significant correlation between VISA-A and T * (r = -0.2; P = 0.17) or VISA-P and T * (r = -0.5; P = 0.0504). Lastly, there was a negative correlation between modulus and T * (r = -0.51; P < 0.05).

Data Conclusions: T * mapping can detect subtle structural changes that translate to altered mechanical properties in early-phase tendinopathy. However, T * did not correlate with clinical scores in patients with early-phase Achilles and patellar tendinopathy. Thus, T * mapping may serve as a tool for early detection of structural changes in tendinopathy but does not necessarily describe the clinical severity of disease.

Level Of Evidence: 1 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27600DOI Listing
March 2021

Clinical Outcomes, Structure, and Function Improve With Both Heavy and Moderate Loads in the Treatment of Patellar Tendinopathy: A Randomized Clinical Trial.

Am J Sports Med 2021 03 22;49(4):982-993. Epub 2021 Feb 22.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg and Frederiksberg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Loading interventions have become a predominant treatment strategy for tendinopathy, and positive clinical outcomes and tendon tissue responses may depend on the exercise dose and load magnitude.

Purpose/hypothesis: The purpose was to investigate if the load magnitude influenced the effect of a 12-week loading intervention for patellar tendinopathy in the short term (12 weeks) and long term (52 weeks). We hypothesized that a greater load magnitude of 90% of 1 repetition maximum (RM) would yield a more positive clinical outcome, tendon structure, and tendon function compared with a lower load magnitude of 55% of 1 RM when the total exercise volume was kept equal in both groups.

Study Design: Randomized clinical trial; Level of evidence, 1.

Methods: A total of 44 adult participants with chronic patellar tendinopathy were included and randomized to undergo moderate slow resistance (MSR group; 55% of 1 RM) or heavy slow resistance (HSR group; 90% of 1 RM). Function and symptoms (Victorian Institute of Sport Assessment-Patella questionnaire [VISA-P]), tendon pain during activity (numeric rating scale [NRS]), and ultrasound findings (tendon vascularization and swelling) were assessed before the intervention, at 6 and 12 weeks during the intervention, and at 52 weeks from baseline. Tendon function (functional tests) and tendon structure (ultrasound and magnetic resonance imaging) were investigated before and after the intervention period.

Results: The HSR and MSR interventions both yielded significant clinical improvements in the VISA-P score (mean ± SEM) (HSR: 0 weeks, 58.8 ± 4.3; 12 weeks, 70.5 ± 4.4; 52 weeks, 79.7 ± 4.6) (MSR: 0 weeks, 59.9 ± 2.5; 12 weeks, 72.5 ± 2.9; 52 weeks, 82.6 ± 2.5), NRS score for running, NRS score for squats, NRS score for preferred sport, single-leg decline squat, and patient satisfaction after 12 weeks, and these were maintained after 52 weeks. HSR loading was not superior to MSR loading for any of the measured clinical outcomes. Similarly, there were no differences in functional (strength and jumping ability) or structural (tendon thickness, power Doppler area, and cross-sectional area) improvements between the groups undergoing HSR and MSR loading.

Conclusion: There was no superior effect of exercising with a high load magnitude (HSR) compared with a moderate load magnitude (MSR) for the clinical outcome, tendon structure, or tendon function in the treatment of patellar tendinopathy in the short term. Both HSR and MSR showed equally good, continued improvements in outcomes in the long term but did not reach normal values for healthy tendons.

Registration: NCT03096067 (ClinicalTrials.gov identifier).
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http://dx.doi.org/10.1177/0363546520988741DOI Listing
March 2021

Collagens in primary frozen shoulder: expression of collagen mRNA isoforms in the different phases of the disease.

Rheumatology (Oxford) 2020 Dec 21. Epub 2020 Dec 21.

Section for Sports Traumatology M51, Department of Orthopaedic Surgery M, Bispebjerg and Frederiksberg Hospital.

Objectives: Primary frozen shoulder (pFS) has three phases that differ in clinical presentation. It is characterized by contracture of the joint capsule. We hypothesized that there is a general upregulation of collagens in pFS, and that this is highest in the first phase of the disease. The aims of this study were to investigate the expression of various collagens and degradation of collagens in patients with primary pFS and relate this to the three phases of the condition.

Methods: From twenty-six patients with pFS and eight control patients with subacromial impingement, biopsies were obtained during shoulder arthroscopy from the middle glenohumeral ligament and the anterior capsule, and mRNA levels for collagens, MMP-2 and -14 and TGF-β1, - β2 and -β3 in the tissue were analysed using real-time PCR.

Results: Genes for collagens type I, III, IV, V, VI and XIV, were activated in pFS, and the total mRNA for all collagens was increased (P < 0.05). This upregulation was independent of disease phases in pFS. In addition, MMP-2, MMP-14, TGF-β1 and TGF-β3 were upregulated in all phases of the disease.

Conclusion: There is a general upregulation and an increased degradation of collagens in pFS in all three phases of the disease. This indicates a constantly increased turnover of the fibrotic tissue in the capsule from pFS. The difference in clinical presentation of pFS observed in the three phases of the disease is not primarily a result of variations in collagen production.
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http://dx.doi.org/10.1093/rheumatology/keaa802DOI Listing
December 2020

Vicariance followed by secondary gene flow in a young gazelle species complex.

Mol Ecol 2021 01 22;30(2):528-544. Epub 2020 Dec 22.

Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, Copenhagen N, Denmark.

Grant's gazelles have recently been proposed to be a species complex comprising three highly divergent mtDNA lineages (Nanger granti, N. notata and N. petersii). The three lineages have nonoverlapping distributions in East Africa, but without any obvious geographical divisions, making them an interesting model for studying the early-stage evolutionary dynamics of allopatric speciation in detail. Here, we use genomic data obtained by restriction site-associated (RAD) sequencing of 106 gazelle individuals to shed light on the evolutionary processes underlying Grant's gazelle divergence, to characterize their genetic structure and to assess the presence of gene flow between the main lineages in the species complex. We date the species divergence to 134,000 years ago, which is recent in evolutionary terms. We find population subdivision within N. granti, which coincides with the previously suggested two subspecies, N. g. granti and N. g. robertsii. Moreover, these two lineages seem to have hybridized in Masai Mara. Perhaps more surprisingly given their extreme genetic differentiation, N. granti and N. petersii also show signs of prolonged admixture in Mkomazi, which we identified as a hybrid population most likely founded by allopatric lineages coming into secondary contact. Despite the admixed composition of this population, elevated X chromosomal differentiation suggests that selection may be shaping the outcome of hybridization in this population. Our results therefore provide detailed insights into the processes of allopatric speciation and secondary contact in a recently radiated species complex.
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http://dx.doi.org/10.1111/mec.15738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898927PMC
January 2021

Age-related myofiber atrophy in old mice is reversed by ten weeks voluntary high-resistance wheel running.

Exp Gerontol 2021 01 9;143:111150. Epub 2020 Nov 9.

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Building 8, 1st floor, Bispebjerg bakke 23, 2400 Copenhagen, NV, Denmark; Center of Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address:

Objective: Age-related loss of muscle mass and function can be attenuated in rodents with life-long voluntary wheel running with moderate resistance. The present study assessed if sarcopenia could be counteracted with ten weeks high intensity training.

Method: Old (22-23 months) and middle-aged (11 months) mice were divided into three physical activity groups: Ten weeks of voluntary running in wheels with high (HR) or low resistance (LR), or no running wheel (SED). The wheel resistance was 0.5-1.5 g in the LR group and progressed from 5 g to 10 g in the HR group. Six, 8 and 5 old and 8, 9 and 9 middle-aged mice of the SED, LR and HR groups, respectively, were included in the analysis. Wheel activity was monitored throughout the intervention. Muscle mass of the tibialis anterior, gastrocnemius, soleus and plantaris muscles were measured post-mortem. Fiber type distribution and myofiber cross sectional areal (CSA) were quantified in the gastrocnemius and soleus muscles as well as total number of fibers in the soleus muscle.

Results: In the SED, the mass of all individual muscles was reduced in the old vs middle-aged (P < 0.001). In the training groups, the old mice ran significantly less, slower and for shorter bouts than the middle-aged throughout the intervention (P < 0.05). HR running increased the gastrocnemius and soleus muscle mass by 6% and 18% respectively in the old compared to SED. Fiber CSA was significantly reduced in the old SED mice, whereas fiber CSA in the old HR gastrocnemius and soleus muscles was comparable to the SED middle-aged. Fiber type shifted from 2b towards 2a in the gastrocnemius muscle of the trained old mice. HR running was more efficient than LR in maintaining muscle mass and myofiber size, and in shifting fiber types. In the middle-aged mice, similar effects were found, but less pronounced. Interestingly, fiber CSA was unaffected by running in the middle-aged.

Conclusion: Ten weeks of HR running had a positive effect on muscle mass and morphology in both middle-aged and old mice. The old HR fiber CSA was greater than in old SED and comparable to the middle-aged, and the fibers shifted to a more oxidative composition (2b → 2a). Albeit less pronounced, similar training effects were observed in the middle-aged mice despite running faster and longer than the old.
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http://dx.doi.org/10.1016/j.exger.2020.111150DOI Listing
January 2021

Proteomics identifies differences in fibrotic potential of extracellular vesicles from human tendon and muscle fibroblasts.

Cell Commun Signal 2020 11 4;18(1):177. Epub 2020 Nov 4.

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Nielsine Nielsens Vej 11, Building 8, Copenhagen, NV, 2400, Denmark.

Background: Fibroblasts are the powerhouses responsible for the production and assembly of extracellular matrix (ECM). Their activity needs to be tightly controlled especially within the musculoskeletal system, where changes to ECM composition affect force transmission and mechanical loading that are required for effective movement of the body. Extracellular vesicles (EVs) are a mode of cell-cell communication within and between tissues, which has been largely characterised in cancer. However, it is unclear what the role of healthy fibroblast-derived EVs is during tissue homeostasis.

Methods: Here, we performed proteomic analysis of small EVs derived from primary human muscle and tendon cells to identify the potential functions of healthy fibroblast-derived EVs.

Results: Mass spectrometry-based proteomics revealed comprehensive profiles for small EVs released from healthy human fibroblasts from different tissues. We found that fibroblast-derived EVs were more similar than EVs from differentiating myoblasts, but there were significant differences between tendon fibroblast and muscle fibroblast EVs. Small EVs from tendon fibroblasts contained higher levels of proteins that support ECM synthesis, including TGFβ1, and muscle fibroblast EVs contained proteins that support myofiber function and components of the skeletal muscle matrix.

Conclusions: Our data demonstrates a marked heterogeneity among healthy fibroblast-derived EVs, indicating shared tasks between EVs of skeletal muscle myoblasts and fibroblasts, whereas tendon fibroblast EVs could play a fibrotic role in human tendon tissue. These findings suggest an important role for EVs in tissue homeostasis of both tendon and skeletal muscle in humans. Video abstract.
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http://dx.doi.org/10.1186/s12964-020-00669-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641822PMC
November 2020

Collagen Growth Pattern in Human Articular Cartilage of the Knee.

Cartilage 2020 Nov 4:1947603520971016. Epub 2020 Nov 4.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M81, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.

Objective: During skeletal growth, the articular cartilage expands to maintain its cover of bones in joints, however, it is unclear when and how cartilage grows. We aim to determine the expanding growth pattern and timing across the tibia plateau in human knees.

Design: Six human tibia plateaus (2 healthy, 2 with osteoarthritis, and 2 with posttraumatic osteoarthritis) were used for full-depth cartilage sampling systematically across the joint surface at 12 medial and 4 lateral sites. Methodologically, we took advantage of the performed nuclear bomb tests in the years 1955 to 1963, which increased the atmospheric C that was incorporated into human tissues. Cartilage was treated enzymatically to extract collagen, analyzed for C content, and year at formation was determined from historical atmospheric C concentrations.

Results: By age-determination, each tibia condyle had central points of formation surrounded by later-formed cartilage toward the periphery. Furthermore, the tibia plateaus contained collagen with C levels corresponding to mean donor age of 11.7 years (±3.8 SD). Finally, the medial condyle had lower C levels corresponding to formation 1 year later than the lateral condyle ( = 0.009).

Conclusions: Human cartilage on the tibia plateau contains collagen that has experienced little if any turnover since school-age. The cartilage formation develops from 2 condyle centers and radially outward with the medial condyle finishing slightly later than the lateral condyle. This suggests a childhood programmed cartilage formation with a very limited adulthood collagen turnover.
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http://dx.doi.org/10.1177/1947603520971016DOI Listing
November 2020

COVID-19 and sports medicine research.

Authors:
Michael Kjaer

Transl Sports Med 2020 Jul 25;3(4):287. Epub 2020 Jun 25.

Institute of Sports Medicine Bispebjerg Hospital University of Copenhagen Denmark.

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http://dx.doi.org/10.1002/tsm2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361378PMC
July 2020

Comparison of Tenocyte Populations from the Core and Periphery of Equine Tendons.

J Proteome Res 2020 10 2;19(10):4137-4144. Epub 2020 Sep 2.

Institute of Sports Medicine Copenhagen, Bispebjerg Hospital and Center for Healthy Aging, University of Copenhagen, 2400 Copenhagen, Denmark.

Tendon is a highly organized, dense connective tissue that has been demonstrated to have very little turnover. In spite of the low turnover, tendon can grow in response to loading, which may take place primarily at the periphery. Tendon injuries and recurrence of injuries are common in both humans and animals in sports. It is unclear why some areas of the tendon are more susceptible to such injuries and whether this is due to intrinsic regional differences in extracellular matrix (ECM) production or tissue turnover. This study aimed to compare populations of tenocytes derived from the tendon core and periphery. Tenocytes were isolated from equine superficial digital flexor tendons (SDFTs), and the proliferation capacity was determined. ECM production was characterized by immuno- and histological staining and by liquid chromatography-mass spectrometry-based proteomics. Core and periphery SDFT cultures exhibited comparable proliferation rates and had very similar proteome profiles, but showed biological variation in collagen type I deposition. In conclusion, the intrinsic properties of tenocytes from different regions of the tendon are very similar, and other factors in the tissue may contribute to how specific areas respond to loading or injury.
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http://dx.doi.org/10.1021/acs.jproteome.0c00591DOI Listing
October 2020

Macrophage Subpopulations and the Acute Inflammatory Response of Elderly Human Skeletal Muscle to Physiological Resistance Exercise.

Front Physiol 2020 24;11:811. Epub 2020 Jul 24.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.

The current model for repair of damaged tissue includes immune cells, mediating the progression from a pro-inflammatory to an anti-inflammatory environment. How this process changes with aging in human skeletal muscle under conditions of physiological exercise loading remains unclear. To investigate this, 25 elderly males (mean age 70 ± SD 7 years), as well as 12 young (23 ± 3 years) and 12 elderly (74 ± 3 years) females, performed a unilateral bout of heavy resistance leg extension exercise. Biopsies were collected from the vastus lateralis muscle of the rested (control) leg, and post exercise from the exercised leg at 4.5 h, and on days 1, 4, and 7 for the male participants, or on day 5 for the female participants. Total macrophages (CD68+) as well as pro- (CD11b+) and anti-inflammatory (CD163+, CD206+) subpopulations were identified on sections by immunohistochemistry. Gene expression levels of COL1A1, TNF-a, CD68, myostatin, TCF7L2, IL-1B, IL-1R, IL-10, and Ki67 were determined by real-time RT-PCR. At rest, the muscle tissue from the elderly vs. young females was characterized by higher gene expression levels of CD68, IL-10, lower myostatin mRNA, and trends for a greater number of macrophages, while COL1A1 mRNA post exercise values were greater in the elderly vs young. For the male participants, mRNA levels of the inflammatory cytokines IL-1B, IL-1R were elevated in the early phase following exercise, followed by increases in COL1A1 and Ki67 on days 4 and 7. In general, exercise induced increases in all types of macrophages counted in the elderly, but not in young, individuals. Cells expressing CD68, CD11b, and CD206 simultaneously were the most frequently observed cell type, which raises the possibility that pure pro- and anti-inflammatory macrophages populations do not exist in healthy human skeletal muscle within the spectrum of tissue remodeling induced by physiological exercise designed to induce hypertrophy. Together these data provide insight into the time course of macrophage activity and associated molecular targets in human skeletal muscle in the context of aging and exercise.
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http://dx.doi.org/10.3389/fphys.2020.00811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393256PMC
July 2020

Maintenance of muscle strength following a one-year resistance training program in older adults.

Exp Gerontol 2020 10 8;139:111049. Epub 2020 Aug 8.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M81 and Center for Translational Research, Bispebjerg and Frederiksberg Hospital, Nielsine Nielsensvej 11, 2400 Copenhagen NV, Denmark; Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Background: Muscle mass, strength and function declines with advancing age. Strength training (ST) improves these parameters in older adults, but the gains often disappear after completion of a short-term intervention. The purpose of the present study was to investigate muscle mass, -strength and -function one year after the completion of a successful long-term (12 months) supervised ST program in older adults.

Method: Men and women (n = 419, age: 62-70 years) completed one year of supervised heavy resistance training (HRT, n = 143) or moderate intensity resistance training (MIT, n = 144) and were compared to a non-exercising control group (CON, n = 132). At 1-year follow-up, 398 participants returned for measurements of muscle power, -strength and -mass, physical function, body composition, hippocampus volume and physical/mental well-being. The results were compared to pre-training (baseline) and post-training (1-year) values. Further, the participants from the two previous training groups (HRT + MIT, n = 265) were divided into 1) those who on their own continued the ST program (>9 months) the year after completion of the supervised ST program (CONTIN, n = 65) and 2) those who stopped during the follow-up year (<9 months) (STOP, n = 200).

Results: Out of all the improvements obtained after the 1-year training intervention, only knee extensor muscle strength in HRT was preserved at 1-year follow-up (p < 0.0001), where muscle strength was 7% higher than baseline. Additionally, the decrease in muscle strength over the second year was lower in CONTIN than in STOP with decreases of 1% and 6%, respectively (p < 0.05). Only in CONTIN was the muscle strength still higher at 1-year follow-up compared with baseline with a 14% increase (p < 0.0001). The heavy strength training induced increase in whole-body lean mass was erased at 1-year follow-up. However, there was a tendency for maintenance of the cross-sectional area of m. vastus lateralis from baseline to 1-year follow-up in HRT compared with CON (p = 0.06). Waist circumference decreased further over the second year in CONTIN, whereas it increased in STOP (p < 0.05).

Conclusion: Even though long-term strength training effectively improved muscle function and other health parameters in older adults, only knee extensor muscle strength was preserved one year after completion of heavy (but not moderate intensity) resistance training. Continuation of strength training resulted in better maintenance of muscle strength and health, which indicates that it is required to continue with physical activity to benefit from the long-term effects of strength training upon muscle function and health in older men and women.
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http://dx.doi.org/10.1016/j.exger.2020.111049DOI Listing
October 2020

What is the impact of acute inflammation on muscle performance in geriatric patients?

Exp Gerontol 2020 09 24;138:111008. Epub 2020 Jun 24.

Department of Orthopaedic Surgery M, Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.

There is growing evidence for a link between loss of skeletal muscle, impaired muscle performance, and systemic markers of acute inflammation in hospitalized geriatric patients. The present literature suggests a negative effect of acute inflammation at the time of hospital admission upon muscle performance and the change of this during the hospital stay, particularly in patients with persistent rather than resolved inflammation. Further, a few studies have reported a positive effect of anti-inflammatory medication upon recovery of muscle function in geriatric patients, but how this is mediated (e.g. inhibition of inflammatory cytokines) is not clear. In conclusion, a negative association between the presence of acute and persistent systemic markers of inflammation and various aspects of muscle function and its recovery after bedrest is observed in geriatric patients.
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http://dx.doi.org/10.1016/j.exger.2020.111008DOI Listing
September 2020

No detectable remodelling in adult human menisci: an analysis based on the C bomb pulse.

Br J Sports Med 2020 Dec 14;54(23):1433-1437. Epub 2020 May 14.

Section for Sportstraumatology M51, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

Objectives: Bone and other human tissues remodel through life, for example, as a response to increasing load, and this prevents permanent destruction of the tissue. Non-traumatic meniscal rupture is a common musculoskeletal disease, but it is unknown if it is caused by inability of the menisci to remodel. The aim of this study was to determine whether meniscal collagen is remodelling throughout life.

Methods: The life-long turnover of the human meniscal collagens was explored by the C bomb pulse method. C levels were determined in menisci from 18 patients with osteoarthritis and 7 patients with healthy knees.

Results: There was a negligible turnover of the meniscal collagen in adults. This low turnover was observed in menisci from patients with knee osteoarthritis and in healthy menisci.

Conclusion: This study provides evidence that essentially no remodelling occurs in the adult human meniscal collagen structure and explains the clinical degeneration that is often seen in menisci of middle-aged and elderly persons. It suggests that strengthening of the collagen structure of menisci, as response to physical activity, may occur during childhood, while it is not possible in the adult population.
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http://dx.doi.org/10.1136/bjsports-2019-101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677461PMC
December 2020

Histology and Function of the Rectus Abdominis Muscle in Patients With Incisional Hernia.

J Surg Res 2020 09 6;253:245-251. Epub 2020 May 6.

Department of Sports Medicine and Orthopedic Surgery, Bispebjerg Hospital and Centre of Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen NV, Denmark.

Background: The aim of the current study was to examine different features of the rectus abdominis muscle (RA) in patients with and without a midline incisional hernia to characterize the effects of a hernia on abdominal wall skeletal muscle.

Material And Methods: RA tissue from patients undergoing surgical repair of a large midline incisional hernia (n = 18) was compared with that from an intact abdominal wall in patients undergoing colorectal resection for benign or low-grade malignant disease (n = 18). In addition, needle biopsies were obtained from the vastus lateralis muscle (VL) of all subjects. Outcome measures were muscle fiber type and size, preoperative truncal flexion strength and leg extension power measured in strength-measure equipment, and RA cross-sectional area measured by computed tomography.

Results: In both the RA and VL, the fiber cross-sectional area was greater in the patients with a hernia. The RA cross-sectional area correlated significantly with the truncal flexion strength (r = 0.44, P = 0.015). Patients in the hernia group had a significantly reduced ratio between truncal flexion strength and RA cross-sectional area compared with the control group (41.3 ± 11.5 N/cmversus 51.2 ± 16.3 N/cm, P = 0.034).

Conclusions: Anatomical displacement of the RA and lack of medial insertion in the linea alba rather than dysfunction secondary to alteration of muscle fiber structure may contribute to impairment of abdominal wall function in patients with midline incisional hernias. The study was registered at http://www.clinicaltrials.gov/(NCT02011048).
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http://dx.doi.org/10.1016/j.jss.2020.03.033DOI Listing
September 2020

UTE T2* mapping of tendinopathic patellar tendons: an MRI reproducibility study.

Acta Radiol 2021 Feb 27;62(2):215-224. Epub 2020 Apr 27.

Department of Radiology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Background: There is currently a lack of imaging modalities that can be used as a sensitive measure in tendinopathy. Recent findings suggest the applicability of ultra-short echo time (UTE) magnetic resonance imaging (MRI) T2* mapping in tendons, but the reproducibility remains unknown.

Purpose: To evaluate test-retest reproducibility of UTE MRI T2* mapping of tendinopathic patellar tendons and to evaluate the intra- and inter-observer reproducibility of the measurement.

Material And Methods: Fifteen patients with chronic patellar tendinopathy were evaluated with UTE MRI twice in a 3.0-T scanner on the same day. Manual segmentation of the patellar tendon was performed by two blinded investigators and automated T2*map reconstruction was performed in custom-made software.

Results: There was a significant and numerically small difference in test-retest T2* values (T2*mean = 0.06 ± 0.07 ms ≈ 3.7%;  = 0.006) with an ICC = 0.91 (95% confidence interval [CI] 0.58-0.98; typical error of 3.0%). The intra- and inter-observer reproducibility showed no significant bias ( = 0.493 and  = 0.052), and generally substantial reproducibility was demonstrated for T2* (intra-observer ICC = 0.99; 95% CI 0.98-1.00 and inter-observer ICC = 0.99; 95% CI 0.96-1.00, and typical error 1.3% and 1.3%, respectively).

Conclusion: These data demonstrate a small bias between repeated measurements for UTE T2*, but with a very low associated mean difference (3.7%) between the two tests. The high ICC values and low typical error % demonstrate reproducibility of repeated T2*-mapping sessions. Further, the method showed substantial intra- and inter-observer reproducibility for T2* values proving feasibility for use of UTE T2* mapping in research and clinical practice.
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http://dx.doi.org/10.1177/0284185120918807DOI Listing
February 2021

The influence of prolonged strength training upon muscle and fat in healthy and chronically diseased older adults.

Exp Gerontol 2020 07 8;136:110939. Epub 2020 Apr 8.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M81 and Centre for Translational Research, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark; Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, N, Denmark.

Background: Physical muscle function and brain hippocampus size declines with age, accelerating after the age of 60. Strength training over a few months improves physical function, but less is known about how long-term strength training affects physical function and hippocampus volume. Therefore, we aimed to investigate the effect of 1-year strength training of two different intensities upon muscle mass, function, and hippocampus volume in retirement-age individuals.

Methods: In this multidisciplinary randomized controlled trial (clinicaltrials.gov: NCT02123641), participants were allocated to either a) supervised, heavy resistance training (HRT, n = 149, 3/wk), b) moderate intensity resistance training (MIT, n = 154, 3/wk) or c) non-exercise activities (CON, n = 148). 451 participants were randomized (62-70 yrs., women 61%, ≈80% with a chronic medical disease) and 419 were included in the intention-to-treat analysis (n = 143, 144 and 132; HRT, MIT and CON). Changes in muscle power (primary outcome), strength and size, physical function, body composition, hippocampus volume and physical/mental well-being were analyzed.

Findings: Of the participants (HRT + MIT), 83% completed training at least 2/week. Leg extensor power was unchanged in all groups, but strength training had a positive effect on isometric knee extensor strength in both groups, whereas an increased muscle mass, cross-sectional area of vastus lateralis muscle, a decreased whole-body fat percentage, visceral fat content and an improved mental health (SF-36) occurred in HRT only. Further, chair-stand performance improved in all groups, whereas hippocampus volume decreased in all groups over time with no influence of strength training.

Interpretation: Together, the results indicate that leg extensor power did not respond to long-term supervised strength training, but this type of training in a mixed group of healthy and chronically diseased elderly individuals can be implemented with good compliance and induces consistent changes in physiological parameters of muscle strength, muscle mass and abdominal fat.
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http://dx.doi.org/10.1016/j.exger.2020.110939DOI Listing
July 2020

Key Components of Human Myofibre Denervation and Neuromuscular Junction Stability are Modulated by Age and Exercise.

Cells 2020 04 6;9(4). Epub 2020 Apr 6.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital, Building 8, Nielsine Nielsens vej 11, 2400 Copenhagen NV, Denmark.

The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in healthy elderly individuals. Participants from two studies (one group of 12 young and 12 elderly females and another group of 25 elderly males) performed a unilateral bout of resistance exercise. Muscle biopsies were collected at 4.5 h and up to 7 days post exercise for tissue analysis and cell culture. Molecular targets related to denervation and NMJ stability were analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction. In addition to a greater presence of denervated fibres, the muscle samples and cultured myotubes from the elderly individuals displayed altered gene expression levels of acetylcholine receptor (AChR) subunits. A single bout of exercise induced general changes in AChR subunit gene expression within the biopsy sampling timeframe, suggesting a sustained plasticity of the NMJ in elderly individuals. These data support the role of exercise in maintaining NMJ stability, even in elderly inactive individuals. Furthermore, the cell culture findings suggest that the transcriptional capacity of satellite cells for AChR subunit genes is negatively affected by ageing.
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http://dx.doi.org/10.3390/cells9040893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226801PMC
April 2020

Preserved capacity for satellite cell proliferation, regeneration, and hypertrophy in the skeletal muscle of healthy elderly men.

FASEB J 2020 05 13;34(5):6418-6436. Epub 2020 Mar 13.

Department of Orthopaedic Surgery M, Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.

Blunted muscle hypertrophy and impaired regeneration with aging have been partly attributed to satellite cell (SC) dysfunction. However, true muscle regeneration has not yet been studied in elderly individuals. To investigate this, muscle injury was induced by 200 electrically stimulated (ES) eccentric contractions of the vastus lateralis (VL) of one leg in seven young (20-31 years) and 19 elderly men (60-73 years). This was followed by 13 weeks of resistance training (RT) for both legs to investigate the capacity for hypertrophy. Muscle biopsies were collected Pre- and Post-RT, and 9 days after ES, for immunohistochemistry and RT-PCR. Hypertrophy was assessed by MRI, DEXA, and immunohistochemistry. Overall, surprisingly comparable responses were observed between the young and elderly. Nine days after ES, Pax7+ SC number had doubled (P < .05), alongside necrosis and substantial changes in expression of genes related to matrix, myogenesis, and innervation (P < .05). Post-RT, VL cross-sectional area had increased in both legs (~15%, P < .05) and SCs/type II fiber had increased ~2-4 times more with ES+RT vs RT alone (P < .001). Together these novel findings demonstrate "youthful" regeneration and hypertrophy responses in human elderly muscle. Furthermore, boosting SC availability in healthy elderly men does not enhance the subsequent muscle hypertrophy response to RT.
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http://dx.doi.org/10.1096/fj.202000196RDOI Listing
May 2020

Regional collagen turnover and composition of the human patellar tendon.

J Appl Physiol (1985) 2020 04 12;128(4):884-891. Epub 2020 Mar 12.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Bispebjerg Hospital, Copenhagen, Denmark.

Tendon pathology (tendinopathy) typically occurs in specific regions of a tendon, and growth in response to exercise also appears to be more pronounced in specific regions. In a previous study in animals we found evidence of regional differences in tendon turnover, but whether the turnover of human patellar tendon differs in different regions still remains unknown. Patellar tendons were obtained from cadavers of healthy men and women (body donation program, = 5 donors, >60 yr of age). Samples were taken from 10 different regions along the length, width, and thickness of the tendon. Turnover was measured by C bomb pulse dating and also estimated from the accumulation of advanced glycation end products (AGEs) by fluorescence (340/460 nm) in addition to measurement of specific AGEs by mass spectrometry. Composition in terms of collagen, glycosaminoglycans (GAGs), and DNA was also assessed in each region. C results showed that all tendon regions had a similar C concentration, which was equal to the average atmospheric C concentration during the first 15 yr of the person's life. Fluorescence normalized to dry weight did not differ between regions, nor did specific AGEs. Higher GAG content was observed in the proximal and near the distal insertion of the tendon. In conclusion, healthy human patellar tendon displays no regional differences in collagen turnover throughout life. Tendon injuries and tendinopathies typically occur in specific regions of the tendon, but the reason for this specificity is not well understood. A potential factor in injury susceptibility is tissue turnover, and previous work suggests that the tendon core has practically no turnover during adult life; however, it is not known whether this is true for other regions of the tendon. Our present results on healthy human patellar tendon clearly demonstrate that turnover does not differ between regions and thereby cannot explain differences in injury susceptibility. The findings also indicate that all regions of the tendon are formed simultaneously during skeletal maturation and do not turn over appreciably during adulthood. This is an important finding because little is known about tendon growth during maturation in humans.
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http://dx.doi.org/10.1152/japplphysiol.00030.2020DOI Listing
April 2020

Influence of the integrin alpha-1 subunit and its relationship with high-fat diet upon extracellular matrix synthesis in skeletal muscle and tendon.

Cell Tissue Res 2020 Jul 28;381(1):177-187. Epub 2020 Feb 28.

Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital, Nielsine Nielsenvej 11, 2400, Copenhagen NV, Denmark.

Integrins are important for mechanosensation in tissue and play, together with nutrition, a role in regulating extracellular matrix (ECM) in skeletal muscle and tendon. Integrin receptors are dimers that consist of an α and β subunit and bridge extracellular and intracellular signals. The present study investigates whether the deletion of the integrin receptor α subunit influences collagen and other matrix proteins in the musculotendinous tissue and whether it causes any compensatory changes in other integrin subunits in C57BL/6J mice. In addition, we study whether a high-fat diet (HFD) influences these responses in muscle or tendon. Mice on a HFD had a higher number of non-enzymatic cross-links in skeletal muscle ECM and increased gene expression of collagen and other extracellular matrix proteins. In contrast to gene expression, total collagen protein content was decreased by HFD in the muscle with no change in tendon. Integrin α subunit knockout resulted in a decrease of collagen type I and III, TGF-β1 and IGF-1 gene expression in muscle of HFD mice but did not affect total collagen protein compared with wild-type (WT) littermates in either muscle or tendon. There was no compensatory increase in the genes that express other integrin subunits. In conclusion, HFD induced a significant increase in expression of ECM genes in muscle. On the protein level, HFD resulted in a lower collagen content in muscle. Tendons were unaffected by the diet. Deletion of the integrin α subunit did not affect collagen protein or gene expression in muscle or tendon.
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http://dx.doi.org/10.1007/s00441-020-03184-yDOI Listing
July 2020
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