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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.

Occupation ratio and fatty infiltration are important parameters for evaluating patients with rotator cuff tears. We analyzed the occupation ratio using a deep-learning framework and studied the fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. To calculate the amount of fatty infiltration of the supraspinatus muscle using an automated region-based Otsu thresholding technique. The mean Dice similarity coefficient, accuracy, sensitivity, specificity, and relative area difference for the segmented lesion, measuring the similarity of clinician assessment and that of a deep neural network, were 0.97, 99.84, 96.89, 99.92, and 0.07, respectively, for the supraspinatus fossa and 0.94, 99.89, 93.34, 99.95, and 2.03, respectively, for the supraspinatus muscle. The fatty infiltration measure using the Otsu thresholding method significantly differed among the Goutallier grades (Grade 0; 0.06, Grade 1; 4.68, Grade 2; 20.10, Grade 3; 42.86, Grade 4; 55.79, p  < 0.0001). The occupation ratio and fatty infiltration using Otsu thresholding demonstrated a moderate negative correlation ( ρ  = − 0.75, p  < 0.0001). This study included 240 randomly selected patients who underwent shoulder magnetic resonance imaging (MRI) from January 2015 to December 2016. We used a fully convolutional deep-learning algorithm to quantitatively detect the fossa and muscle regions by measuring the occupation ratio of the supraspinatus muscle. Fatty infiltration was objectively evaluated using the Otsu thresholding method. The proposed convolutional neural network exhibited fast and accurate segmentation of the supraspinatus muscle and fossa from shoulder MRI, allowing automatic calculation of the occupation ratio. Quantitative evaluation using a modified Otsu thresholding method can be used to calculate the proportion of fatty infiltration in the supraspinatus muscle. We expect that this will improve the efficiency and objectivity of diagnoses by quantifying the index used for shoulder MRI.

Background To evaluate paraspinal back muscles of asymptomatic subjects using qualitative and quantitative analysis on CT and MRI and correlate the results with demographic data. Methods Twenty-nine asymptomatic subjects were enrolled prospectively (age: mean 34.31, range 23–50; 14 men, 15 women) from August 2016 to April 2017. Qualitative analysis of muscles was done using Goutallier’s system on CT and MRI. Quantitative analysis entailed cross sectional area (CSA) on CT and MRI, Hounsfield unit (HU) on CT, fat fraction using two-point Dixon technique on MRI. Three readers independently analyzed the images; intra- and inter-observer agreements were measured. Linear regression and Spearman’s analyses were used for correlation with demographic data. Results CSA values were significantly higher in men ( p  < 0.001). Fat fraction was higher (22.53% vs. 14.35%) and HU lower (36.00 vs. 47.43) in women ( p  < 0.001). Intra- and inter-observer reliabilities of the two methods were greater than 0.8, except for CSA of L5/S1 on MRI; however, regarding quantitative analysis, decreasing HU and increasing fat fraction were correlated with increasing age, female gender and lower lumbar segment ( p  < 0.001). Conclusion MRI and CT can be reliably used for qualitative and quantitative analysis of paraspinal back muscles, regarding fat content. Fat fraction and HU showed highest reliabilities.

By the year 2030, 3.48 million older U.S. adults are projected to undergo total knee arthroplasty (TKA). Following this surgery, considerable muscle atrophy occurs, resulting in decreased strength and impaired functional mobility. Essential amino acids (EAAs) have been shown to attenuate muscle loss during periods of reduced activity and may be beneficial for TKA patients. We used a double-blind, placebo-controlled, randomized clinical trial with 28 older adults undergoing TKA. Patients were randomized to ingest either 20 g of EAAs (n = 16) or placebo (n = 12) twice daily between meals for 1 week before and 2 weeks after TKA. At baseline, 2 weeks, and 6 weeks after TKA, an MRI was performed to determine mid-thigh muscle and adipose tissue volume. Muscle strength and functional mobility were also measured at these times. TKA patients receiving placebo exhibited greater quadriceps muscle atrophy, with a -14.3 ± 3.6% change from baseline to 2 weeks after surgery compared with -3.4 ± 3.1% for the EAA group (F = 5.16, P = 0.036) and a -18.4 ± 2.3% change from baseline to 6 weeks after surgery for placebo versus -6.2 ± 2.2% for the EAA group (F = 14.14, P = 0.001). EAAs also attenuated atrophy in the nonoperated quadriceps and in the hamstring and adductor muscles of both extremities. The EAA group performed better at 2 and 6 weeks after surgery on functional mobility tests (all P < 0.05). Change in quadriceps muscle atrophy was significantly associated with change in functional mobility (F = 5.78, P = 0.021). EAA treatment attenuated muscle atrophy and accelerated the return of functional mobility in older adults following TKA. Clinicaltrials.gov NCT00760383.

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 Muscle disuse from bed rest or spaceflight results in losses in muscle mass, strength and oxidative capacity. Capillary rarefaction may contribute to muscle atrophy and the reduction in oxidative capacity during bed rest. Artificial gravity may attenuate the negative effects of long‐term space missions or bed rest. The aim of the present study was to assess (1) the effects of bed rest on muscle fibre size, fibre type composition, capillarization and oxidative capacity in the vastus lateralis and soleus muscles after 6 and 55 days of bed rest and (2) the effectiveness of artificial gravity in mitigating bed‐rest‐induced detriments to these parameters. Methods Nineteen participants were assigned to a control group (control, n = 6) or an intervention group undergoing 30 min of centrifugation (n = 13). All underwent 55 days of head‐down tilt bed rest. Vastus lateralis and soleus biopsies were taken at baseline and after 6 and 55 days of bed rest. Fibre type composition, fibre cross‐sectional area, capillarization indices and oxidative capacity were determined. Results After just 6 days of bed rest, fibre atrophy (−23.2 ± 12.4%, P < 0.001) and reductions in capillary‐to‐fibre ratio (C:F; 1.97 ± 0.57 vs. 1.56 ± 0.41, P < 0.001) were proportional in both muscles as reflected by a maintained capillary density. Fibre atrophy proceeded at a much slower rate between 6 and 55 days of bed rest (−11.6 ± 12.1% of 6 days, P = 0.032) and was accompanied by a 19.1% reduction in succinate dehydrogenase stain optical density (P < 0.001), without any further significant decrements in C:F (1.56 ± 0.41 vs. 1.49 ± 0.37, P = 0.459). Consequently, after 55 days of bed rest, the capillary supply–oxidative capacity ratio of a fibre had increased by 41.9% (P < 0.001), indicating a capillarization in relative excess of oxidative capacity. Even though the heterogeneity of capillary spacing (LogRSD) was increased after 55 days by 12.7% (P = 0.004), tissue oxygenation at maximal oxygen consumption of the fibres was improved after 55 days bed rest. Daily centrifugation failed to blunt the bed‐rest‐induced reductions in fibre size and oxidative capacity and capillary rarefaction. Conclusions The relationship between fibre size and oxidative capacity with the capillary supply of a fibre is uncoupled during prolonged bed rest as reflected by a rapid loss of muscle mass and capillaries, followed at later stages by a more than proportional loss of mitochondria without further capillary loss. The resulting excessive capillary supply of the muscle after prolonged bed rest is advantageous for the delivery of substrates needed for subsequent muscle recovery.

Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.

Background Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization. Methods In this double‐blind, placebo‐controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full‐length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter‐muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. Results Casting resulted in an average TMV loss of −4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre‐cast levels at 12 weeks. In comparison, TMV returned to pre‐cast level at 12 weeks (−0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: −6.6%, SCAT: −3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre‐cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. Conclusions A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint‐immobilizing cast.

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.

Purpose Applying blood flow restriction during low-load resistance training has been shown to augment muscle hypertrophy which has been attributed to metabolic accumulation. It remains unknown, however, whether metabolites can augment muscle growth when maintained post-exercise. Methods Thirteen untrained individuals (6 males and 7 females) performed 24 training sessions. The control arm performed one set of elbow flexion (70 % 1RM) to volitional fatigue, while the experimental arm performed the same protocol immediately followed by 3 min of blood flow restriction (70 % arterial occlusion). Muscle growth (ultrasound) was measured at 50, 60, and 70 % of the distance between the lateral epicondyle and acromion process. Results Both conditions completed the same exercise volume [3678 (95 % CI 2962, 4393) vs. 3638 kg (95 % CI 2854, 4423)]. There was a condition by time interaction ( p  = 0.031) demonstrating an attenuation of muscle growth at the 60 % site in the experimental [pre 3.1 (95 % CI 2.8, 3.5), post 3.1 (95 % CI 2.7, 3.5) cm] vs. control [pre 3.1 (95 % CI 2.6, 3.6), post 3.3 (95 % CI 2.8, 3.7) cm] condition. Muscle growth at the 50 % and 70 % sites was similar at the group level, although there were attenuations at the individual level. Exploratory analyses of pre–post mean (95 % CI) changes in muscle thickness suggested that this attenuation in the experimental condition occurred only in females [50 % site 0.0 (−0.2, 0.0) cm; 60 % site −0.1 (−0.3, 0.0) cm; 70 % site 0.0 (−0.1, 0.1) cm]. Conclusions The application of blood flow restriction post high-load training did not augment muscle growth for either sex, and appeared to attenuate muscle growth among females.