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Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3–IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3–IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD G93A mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases. Madaro et al. show that denervation induces accumulation of IL-6–STAT3-activated fibro-adipogenic progenitors without inflammation or muscle regeneration, leading to muscle atrophy and fibrosis.

Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators. To assess the effects of bimagrumab on skeletal muscle mass and function in patients with chronic obstructive pulmonary disease (COPD) and reduced skeletal muscle mass. Sixty-seven patients with COPD (mean FEV , 1.05 L [41.6% predicted]; aged 40-80 yr; body mass index < 20 kg/m or appendicular skeletal muscle mass index ≤ 7.25 [men] and ≤ 5.67 [women] kg/m ), received two doses of either bimagrumab 30 mg/kg intravenously (n = 33) or placebo (n = 34) (Weeks 0 and 8) over 24 weeks. We assessed changes in thigh muscle volume (cubic centimeters) as the primary endpoint along with 6-minute-walk distance (meters), safety, and tolerability. Fifty-five (82.1%) patients completed the study. Thigh muscle volume increased by Week 4 and remained increased at Week 24 in bimagrumab-treated patients, whereas no changes were observed with placebo (Week 4: +5.9% [SD, 3.4%] vs. 0.0% [3.3%], P < 0.001; Week 8: +7.0% [3.7%] vs. -0.7% [2.8%], P < 0.001; Week 16: +7.8% [5.1%] vs. -0.9% [4.5%], P < 0.001; Week 24: +5.0% [4.9%] vs. -1.3% [4.3%], P < 0.001). Over 24 weeks, 6-minute-walk distance did not increase significantly in either group. Adverse events in the bimagrumab group included muscle-related symptoms, diarrhea, and acne, most of which were mild in severity. Blocking the action of negative muscle regulators through the activin type II receptors with bimagrumab treatment safely increased skeletal muscle mass but did not improve functional capacity in patients with COPD and low muscle mass. Clinical trial registered with www.clinicaltrials.gov (NCT01669174).

Background Extensive muscle atrophy is a common occurrence in orthopaedics patients who are bedridden or immobilized. The incidence is higher in intensive care unit (ICU) inpatients. There is still controversy about how to use neuromuscular electrical stimulation (NMES) in ICU patients. We aim to compare the effectiveness and safety of NMES to prevent muscle atrophy in intensive care unit (ICU) patients without nerve injury. Methods ICU patients without central and peripheral nerve injury were randomized into experimental group I (Exp I: active and passive activity training (APAT) + NMES treatment on the gastrocnemius and tibialis anterior muscle), experimental group II (Exp II: APAT + NMES treatment on gastrocnemius alone), and control group (Ctl: APAT alone). Changes in the strength of gastrocnemius, the ankle range of motion, and the muscle cross-section area of the lower leg were evaluated before and after the intervention. Also, changes in prothrombin time, lactic acid, and C-reactive protein were monitored during the treatment. Results The gastrocnemius muscle strength, ankle joint range of motion, and cross-sectional muscle area of the lower leg in the three groups showed a downward trend, indicating that the overall trend of muscle atrophy in ICU patients was irreversible. The decrease in gastrocnemius muscle strength in Exp I and Exp II was smaller than that in the control group ( P  < 0.05), but there was no difference between Exp I and Exp II. The decrease in active ankle range of motion and cross-sectional area of the lower leg Exp I and Exp II was smaller than that in the control group ( P  < 0.05), and the decrease in Exp I was smaller than that of Exp II (all P  < 0.05). The curative effect in Exp I was better than in Exp II. There were no significant differences in the dynamic changes of prothrombin time, lactic acid, and C-reactive protein during the three groups ( P  > 0.05). Conclusion In addition to early exercise training, NMES should be applied to prevent muscle atrophy for patients without nerve injury in ICU. Also, simultaneous NMES treatment on agonist/antagonist muscle can enhance the effect of preventing muscle atrophy. Trial registration This study was prospectively registered in China Clinical Trial Registry ( www.chictr.org.cn ) on 16/05/2020 as ChiCTR2000032950.

Exacerbations of chronic obstructive pulmonary disease (COPD) acutely reduce skeletal muscle strength and result in long-term loss of functional capacity. To investigate whether resistance training is feasible and safe and can prevent deteriorating muscle function during exacerbations of COPD. Forty patients (FEV(1) 49 +/- 17% predicted) hospitalized with a severe COPD exacerbation were randomized to receive usual care or an additional resistance training program during the hospital admission. Patients were followed up for 1 month after discharge. Primary outcomes were quadriceps force and systemic inflammation. A muscle biopsy was taken in a subgroup of patients to assess anabolic and catabolic pathways. Resistance training did not yield higher systemic inflammation as indicated by C-reactive protein levels and could be completed uneventfully. Enhanced quadriceps force was seen at discharge (+9.7 +/- 16% in the training group; -1 +/- 13% in control subjects; P = 0.05) and at 1 month follow-up in the patients who trained. The 6-minute walking distance improved after discharge only in the group who received resistance training (median 34; interquartile range, 14-61 m; P = 0.002). In a subgroup of patients a muscle biopsy showed a more anabolic status of skeletal muscle in patients who followed training. Myostatin was lower (P = 0.03) and the myogenin/MyoD ratio tended to be higher (P = 0.08) in the training group compared with control subjects. Resistance training is safe, successfully counteracts skeletal muscle dysfunction during acute exacerbations of COPD, and may up-regulate the anabolic milieu in the skeletal muscle. Clinical trial registered with www.clinicaltrials.gov (NCT00877084).

Background Critically ill patients rapidly loose much of their muscle mass and strength. This can be attributed to prolonged admission, prolonged mechanical ventilation and increased mortality, and it can have a negative impact on the degree of independence and quality of life. In the NONSEDA trial we randomize critically ill patients to non-sedation or sedation with a daily wake-up trial during mechanical ventilation in the intensive care unit. It has never been assessed whether non-sedation affects physical function. The aim of this study is to assess the effects of non-sedation versus sedation with a daily wake-up trial on physical function after discharge from intensive care unit. Methods/Design Investigator-initiated, randomized, clinical, parallel-group, superiority trial, including 700 patients in total, with a substudy concerning 200 of these patients. Inclusion criteria will be intubated, mechanically ventilated patients with expected duration of mechanical ventilation >24 h. Exclusion criteria will be patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO 2 /FiO 2 <9 where sedation might be necessary to ensure sufficient oxygenation or placing the patient in a prone position. The experimental intervention will be non-sedation supplemented with pain management during mechanical ventilation. The control intervention will be sedation with a daily wake-up trial. The co-primary outcome will be quality of life regarding physical function (SF-36, physical component) and degree of independence in activities of daily living (Barthel Index), and this will be assessed for all 700 patients participating in the NONSEDA trial. The secondary outcomes, which will be assessed for the subpopulation of 200 NONSEDA patients in the trial site, Kolding, will be 6-min walking distance, handgrip strength, muscle size (ultrasonographic measurement of the rectus femoris muscle cross-sectional area) and biomechanical data on lower extremity function (maximal voluntary contraction, rate of force development and endurance). Discussion This study is the first to investigate the effect of no sedation during critical illness on physical function. If an effect is found, it will add important information on how to prevent muscle weakness following critical illness. Trial registration The study has been approved by the relevant scientific ethics committee and is registered at ClinicalTrials.gov (ID: NCT02034942 , 9 January 2014).

Background Ventilator-induced diaphragmatic dysfunction (VIDD) occurs in up to 60% of mechanically ventilated patients and prolongs ventilatory dependance. The consequences of VIDD are muscle atrophy, reduction of strength, and injury of muscle fibers. Atrophy and contractile activity of the diaphragm can be estimated by ultrasound muscle thickness and thickening fraction. Prior experience demonstrates invasive electrical stimulation of the diaphragm helps preserve muscle thickness. This is the first study on a non-invasive phrenic nerve stimulator that aims to assess its feasibility, safety, and usefulness in preserving diaphragm thickness. Methods A multi-center randomized clinical trial will be performed in four intensive care units (ICUs) in the United States of America and Canada. Inclusion criteria include patients older than 21 years, in the first 48 h of mechanical ventilation (MV) and predicted to remain on the ventilator for at least 48 h. Patients with contraindications for phrenic nerve stimulation, severe chronic pulmonary diseases, or impossibility to measure diaphragm thickness with ultrasound will be excluded. Patients enrolled will be randomized to standard care (control) or 30-min daily non-invasive phrenic nerve stimulation up to 10 days after enrollment (intervention). The primary effectiveness endpoint is the change in diaphragm thickness on day 10, extubation, or death whichever occurs first. Secondary endpoints include change in diaphragm thickness on day 4, maximal inspiratory pressure before extubation, and time-to rapid shallow breathing index (RSBI) <105. Safety objectives include the proportion of device- or procedure-related adverse events (SAE). The estimated sample size will be 40 patients (20 per group). Discussion The STIMIT ACTIVATOR trial is a randomized multi-center study powered to elucidate whether non-invasive phrenic nerve stimulation is feasible, safe, and preserves diaphragm thickness. Meeting the primary endpoint will demonstrate its applicability in clinical practice to prevent diaphragmatic atrophy in ventilated patients. Trial registration ClinicalTrials.gov: NCT05883163, August 29, 2023.

Introduction Pain management and prevention of muscle atrophy are key rehabilitation challenges following arthroscopic rotator cuff repair (ARCR). Despite the potential muscle atrophy-reducing and analgesic effects of neuromuscular electrical stimulation (NMES), evidence supporting its use in post-ARCR rehabilitation remains limited. This study aimed to evaluate the clinical efficacy of home-based NMES intervention for promoting early functional recovery after ARCR. Methods A total of 63 ARCR patients were randomized into the NMES group ( n  = 32) and MENS (Micro-current electrical nerve stimulation) group ( n  = 31), both receiving a 6-week home-based intervention (5 sessions weekly, 30 min per session) following surgery. The NMES group used neuromuscular electrical stimulation equipment, while the MENS group used identical devices without current output. The primary outcome was the Constant-Murley Shoulder (CMS) score, with secondary outcomes including resting and active visual analog scale (VAS) pain scores, deltoid muscle thicknes, shoulder range of motion (ROM), muscle strength, and Tampa Scale for Kinesiophobia scores. Assessments were conducted preoperatively, at 6 weeks, and 3 months postoperatively. Results At 6 weeks postoperatively, the NMES group exhibited a significantly higher CMS than the MENS group (76.10 ± 9.43 vs. 71.22 ± 9.2 p  = 0.032), along with superior active pain relief (active VAS: 4.1 ± 0.9 vs. 3.4 ± 0.7 p  = 0.003), greater forward flexion ROM (151.7 ± 11.3 vs. 141.8 ± 13.6 p  = 0.003), and thicker deltoid muscle thickness (1.02 ± 0.06 vs. 0.91 ± 0.06 p  < 0.001). The NMES group also demonstrated lower TSK scores (31.06 ± 6.69 vs. 35.42 ± 7.76 p  = 0.020) and greater adductor strength (40.9 ± 16.7 vs. 33.5 ± 12.2 p  = 0.048). By 3 months postoperatively, intergroup differences persisted only in abductor ROM, muscle strength, and deltoid thickness, with no significant disparities in other measured indices. Conclusions Home-based NMES effectively accelerates functional recovery, enhances pain management, and mitigates kinesiophobia within 6 weeks post-ARCR, with partial maintenance of these benefits at the 3-month follow-up. This intervention offers a safe adjunctive strategy for early rehabilitation, particularly suited to patients requiring rapid functional restoration; however, long-term efficacy remains to be confirmed.To evaluate the acceptability of MyCheck for asymptomatic sexually transmissible infections (STIs) testing. Trial registration (Chinese Clinical Trial Registry ( https://www.chictr.org.cn ), No. ChiCTR2400088194, 13/08/2024)

Background Patients diagnosed with pancreatic, biliary tract, and liver cancer often suffer from a progressive loss of muscle mass. Given the considerable functional impairments in these patients, high musculoskeletal weight loads may not be well tolerated by all individuals. The use of blood-flow restricted resistance training (BFR-T) which only requires low training loads may allow for a faster recovery of muscle due to avoidance of high levels of mechanical muscle stress associated with high-load resistance exercise. This study aims to investigate whether BFR-T can prevent or slow down the loss of skeletal muscle mass and enhance the functional capacity and mental health of patients with pancreatic, biliary tract, and liver cancer. Methods The PREV-Ex exercise trial is a multicenter two-armed randomized controlled trial. Patients will be randomized to an exercise program consisting of home-based low-load BFR-T during a combined pre- and postoperative period for a total of 6–10 weeks (prehabilitation and rehabilitation), or to a control group. Protein supplementation will be given to both groups to ensure adequate protein intake. The primary outcomes, skeletal muscle thickness and muscle cross-sectional area, will be assessed by ultrasound. Secondary outcomes include the following: (i) muscle catabolism-related and inflammatory bio-markers (molecular characteristics will be assessed from a vastus lateralis biopsy and blood samples will be obtained from a sub-sample of patients); (ii) patient-reported outcome measures (self-reported fatigue, health-related quality of life, and nutritional status will be assessed through validated questionnaires); (iii) physical fitness/performance/activity (validated tests will be used to evaluate physical function, cardiorespiratory fitness and maximal isometric muscle strength. Physical activity and sedentary behavior (assessed using an activity monitor); (iv) clinical outcomes: hospitalization rates and blood status will be recorded from the patients’ medical records; (v) explorative outcomes of patients’ experience of the exercise program which will be evaluated using focus group/individual interviews. Discussion It is worthwhile to investigate new strategies that have the potential to counteract the deterioration of skeletal muscle mass, muscle function, strength, and physical function, all of which have debilitating consequences for patients with pancreatic, biliary tract, and liver cancer. The expected findings could improve prognosis, help patients stay independent for longer, and possibly reduce treatment-related costs. Trial registration ClinicalTrials.gov NCT05044065. Registered on September 14, 2021.

Background and Objectives: Muscle atrophy caused by chronic ankle instability (CAI) can incur muscle weakness, altered movement patterns, and increased risk of injury. Previous studies have investigated the effects of rehabilitative exercises and neuromuscular electrical stimulation (NMES) on characteristics in CAI individuals, but few studies have examined their effects on foot and ankle muscle morphology. This study aimed to determine the effects of rehabilitative exercises and NMES on muscle morphology and dynamic balance in individuals with CAI. Materials and Methods: Participants with CAI (n = 47) were randomly divided into control (CG), rehabilitative exercise (REG), NMES (NG), and rehabilitative exercise and NMES combined (RNG) groups. The six-week intervention program consisting of rehabilitative exercises and NMES was applied to groups excluding CG. Muscle morphology and dynamic balance were evaluated using a portable wireless diagnostic ultrasound device and dynamic balance tests. For statistical analysis, an effect size with 95% confidence interval was calculated to assess mean differences according to intervention. Results: After six weeks, significant increases in morphology and dynamic balance were observed for all muscles except flexor hallucis longus (p > 0.05) in the intervention groups except for CG. However, no significant changes were observed in the CG (p > 0.05). Conclusions: These findings suggest that intervention programs may help prevent muscle atrophy and improve balance in CAI individuals.

Background: Short successive periods of physical inactivity occur throughout life and contribute considerably to the age-related loss of skeletal muscle mass. The maintenance of muscle mass during brief periods of disuse is required to prevent functional decline and maintain metabolic health. Objective: To assess whether daily leucine supplementation during a short period of disuse can attenuate subsequent muscle loss in vivo in humans. Methods: Thirty healthy (22 ± 1 y) young males were exposed to a 7-day unilateral knee immobilization intervention by means of a full leg cast with (LEU, n = 15) or without (CON, n = 15) daily leucine supplementation (2.5 g leucine, three times daily). Prior to and directly after immobilization, quadriceps muscle cross-sectional area (computed tomography (CT) scan) and leg strength (one-repetition maximum (1-RM)) were assessed. Furthermore, muscle biopsies were taken in both groups before and after immobilization to assess changes in type I and type II muscle fiber CSA. Results: Quadriceps muscle cross-sectional area (CSA) declined in the CON and LEU groups (p < 0.01), with no differences between the two groups (from 7712 ± 324 to 7287 ± 305 mm2 and from 7643 ± 317 to 7164 ± 328 mm2; p = 0.61, respectively). Leg muscle strength decreased from 56 ± 4 to 53 ± 4 kg in the CON group and from 63 ± 3 to 55 ± 2 kg in the LEU group (main effect of time p < 0.01), with no differences between the groups (p = 0.052). Type I and II muscle fiber size did not change significantly over time, in both groups (p > 0.05). Conclusions: Free leucine supplementation with each of the three main meals (7.5 g/d) does not attenuate the decline of muscle mass and strength during a 7-day limb immobilization intervention.