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Objectives The aim of the study were to (1) investigate what physical and physiological parameters are most important for Frame Running capacity, a parasport for individuals with ambulatory difficulties, and (2) determine whether Frame Running capacity can be predicted in athletes with cerebral palsy. Design Athletes with cerebral palsy (N = 62, Gross Motor Classification System I–V; 2/26/11/21/2) completed a 6-min Frame Running test. Before the 6-min Frame Running test, muscle thickness, passive range of motion (hip, knee, ankle), selective motor control, and spasticity (hip, knee, ankle) were measured in both legs. In total, 54 variables per individual were included. Data were analyzed using correlations, principal component analysis, orthogonal partial least square regression, and variable importance in projection analysis. Results The mean 6-min Frame Running test distance was 789 ± 335 m and decreased with motor function severity. The orthogonal partial least square analysis revealed a modest degree of covariance in the variables analyzed and that the variance in the 6-min Frame Running test distance could be predicted with 75% accuracy based on all the variables measured. Variable importance in projection analysis indicated hip and knee extensor spasticity (negative effect), and muscle thickness (positive effect) arose as the most important factors contributing to Frame Running capacity. Conclusions These results are an important resource to enable optimization of training regimes to improve Frame Running capacity and contribute to evidence-based and fair classification for this parasport., OBJECTIVES: The aim of the study were to (1) investigate what physical and physiological parameters are most important for Frame Running capacity, a parasport for individuals with ambulatory difficulties, and (2) determine whether Frame Running capacity can be predicted in athletes with cerebral palsy. DESIGN: Athletes with cerebral palsy ( N = 62, Gross Motor Classification System I-V; 2/26/11/21/2) completed a 6-min Frame Running test. Before the 6-min Frame Running test, muscle thickness, passive range of motion (hip, knee, ankle), selective motor control, and spasticity (hip, knee, ankle) were measured in both legs. In total, 54 variables per individual were included. Data were analyzed using correlations, principal component analysis, orthogonal partial least square regression, and variable importance in projection analysis. RESULTS: The mean 6-min Frame Running test distance was 789 ± 335 m and decreased with motor function severity. The orthogonal partial least square analysis revealed a modest degree of covariance in the variables analyzed and that the variance in the 6-min Frame Running test distance could be predicted with 75% accuracy based on all the variables measured. Variable importance in projection analysis indicated hip and knee extensor spasticity (negative effect), and muscle thickness (positive effect) arose as the most important factors contributing to Frame Running capacity. CONCLUSIONS: These results are an important resource to enable optimization of training regimes to improve Frame Running capacity and contribute to evidence-based and fair classification for this parasport.

Cumulative evidence supports the hypothesis that hypoxia acts as a regulator of muscle mass. However, the underlying molecular mechanisms remain incompletely understood, particularly in human muscle. Here we examined the effect of hypoxia on signaling pathways related to ribosome biogenesis and myogenic activity following an acute bout of resistance exercise. We also investigated whether hypoxia influenced the satellite cell response to resistance exercise. Employing a randomized, crossover design, eight men performed resistance exercise in normoxia (FiO2 21%) or normobaric hypoxia (FiO2 12%). Muscle biopsies were collected in a time-course manner (before, 0, 90, 180 min and 24 h after exercise) and were analyzed with respect to cell signaling, gene expression and satellite cell content using immunoblotting, RT-qPCR and immunofluorescence, respectively. In normoxia, resistance exercise increased the phosphorylation of RPS6, TIF-1A and UBF above resting levels. Hypoxia reduced the phosphorylation of these targets by ~37%, ~43% and ~ 67% throughout the recovery period, respectively (p < .05 vs. normoxia). Resistance exercise also increased 45 S pre-rRNA expression and mRNA expression of c-Myc, Pol I and TAF-1A above resting levels, but no differences were observed between conditions. Similarly, resistance exercise increased mRNA expression of myogenic regulatory factors throughout the recovery period and Pax7+ cells were elevated 24 h following exercise in mixed and type II muscle fibers, with no differences observed between normoxia and hypoxia. In conclusion, acute hypoxia attenuates ribosome signaling, but does not impact satellite cell pool expansion and myogenic gene expression following a bout of resistance exercise in human skeletal muscle.

Introduction and aims: Accurate determination of skeletal muscle size is of great importance in multiple settings including resistance exercise, aging, disease, and disuse. Ultrasound (US) measurement of muscle thickness (MT) is a method of relatively high availability and low cost. The present study aims to evaluate a multisite ultrasonographic protocol for measurement of MT with respect to reproducibility and correlation to gold-standard measurements of muscle volume (MV) with magnetic resonance imaging (MRI) in children.Material and methods: 15 children completed the study (11 +/- 1 year, 41 +/- 8 kg, 137 +/- 35 cm). Following 20 min supine rest, two investigators performed US MT measurements of all four heads of the m. quadriceps femoris, at pre-determined sites. Subsequently, MRI scanning was performed and MV was estimated by manual contouring of individual muscle heads.Results: Ultrasound measurement of MT had an intra-rater reliability of ICC = 0.985-0.998 (CI 95% = 0.972-0.998) and inter-rater reliability of ICC = 0.868-0.964 (CI 95% = 0.637-0.983). The US examinations took less than 15 min, per investigator. Muscle thickness of all individual quadriceps muscles correlated significantly with their corresponding MV as measured by MRI (overall r = 0.789, p < 0.001).Conclusion: The results of this study indicate that US measurement of MT using a multisite protocol is a competitive alternative to MRI scanning, especially with respect to availability and time consumption. Therefore, US MT could allow for wider clinical and scientific implementation.

Introduction The ischaemic pain of acute compartment syndrome (ACS) can be difficult to discriminate from the pain linked to an associated fracture. Lacking objective measures, the decision to perform fasciotomy is based on clinical findings and performed at a low level of suspicion. Biomarkers of muscle cell damage may help to identify and monitor patients at risk, similar to current routines for patients with acute myocardial infarction. This study will test the hypothesis that biomarkers of muscle cell damage can predict ACS in patients with tibial fractures. Methods and analysis Patients aged 15-65 years who have suffered a tibial fracture will be included. Plasma (P)-myoglobin and P-creatine phosphokinase will be analysed at 6-hourly intervals after admission to the hospital (for 48 hours) and-if applicable-after surgical fixation or fasciotomy (for 24 hours). In addition, if ACS is suspected at any other point in time, blood samples will be collected at 6-hourly intervals. An independent expert panel will assess the study data and will classify those patients who had undergone fasciotomy into those with ACS and those without ACS. All primary comparisons will be perforated between fracture patients with and without ACS. The area under the receiver operator characteristics curves will be used to identify the success of the biomarkers in discriminating between fracture patients who develop ACS and those who do not. Logistic regression analyses will be used to assess the discriminative abilities of the biomarkers to predict ACS corrected for prespecified covariates. Ethics and dissemination The study has been approved by the Regional Ethical Review Boards in Linkoping (2017/514-31) and Helsinki/Uusimaa (HUS/2500/2000). The BioFACTS study will be reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology recommendations., Funding Agencies|Linkoping University, Region Ostergotland [RO-969530, RO-941258, RO-892721, RO-785751]; Medical Research Council of Southeast Sweden [FORSS-852501, FORSS-939750, FORSS--706601, RALF-0600911]; Wallenberg Foundation; Futurum-the Academy for Health and Care, Region Jonkoping County, Sweden [FUTURUM-937508, 870471]; Finnish state funding for university-level health research

Circulating microRNAs (miRNAs) have become increasingly popular biomarker candidates in various diseases. However, heparin-based anticoagulants might affect the detection of target miRNAs in blood samples during quantitative polymerase chain reaction (qPCR)-based analysis of miRNAs involving RNA extraction, cDNA synthesis and the polymerase catalyzed reaction. Because low-molecular-weight heparins (LMWH) are widely used in routine healthcare, we aimed to investigate whether a prophylactic dose of the LMWH tinzaparin influences qPCR-based quantification of circulating miRNAs. A total of 30 subjects were included: 16 fracture patients with tinzaparin treatment and 14 non-fracture controls without anticoagulation therapy. To control for the effect of tinzaparin on miRNA analysis an identical concentration of synthetic miRNAs was added to plasma, isolated RNA and prepared complementary DNA (cDNA) from all samples in both groups. No significant difference was observed for cDNA synthesis or qPCR when comparing tinzaparin-treated patients with untreated controls. Among the tinzaparin-treated patients, plasma levels of six endogenous miRNAs (hsa-let-7i-5p, hsa-miR-30e-5p, hsa-miR-222-3p, hsa-miR-1-3p, hsa-miR-133a-3p, hsa-miR-133b) were measured before and one to six hours after a subcutaneous injection of tinzaparin 4500IU. No significant effect was observed for any of the investigated miRNAs. A prophylactic dose of 4500IU tinzaparin does not seem to affect cDNA synthesis or qRT-PCR-based quantification of circulating miRNAs., Funding Agencies|Linkoping University; Medical Research Council of Southeast Sweden [FORSS-852501]; Futurum - the Academy for Health and Care, Region Jonkoping County, Sweden [FUTURUM-937508, 870471]; Swedish Kidney Foundation [F2019-0048]; Knut and Alice Wallenberg Foundation; Region Ostergotland

In this study, the properties of circulating extracellular vesicles (EVs) were examined in cerebral palsy (CP) and typically developed (TD) individuals at rest and after aerobic exercise, focusing on the size, concentration, and microRNA cargo of EVs. Nine adult individuals with CP performed a single exercise bout consisting of 45 min of Frame Running, and TD participants completed either 45 min of cycling (n = 10; TD EX) or were enrolled as controls with no exercise (n = 10; TD CON). Blood was drawn before and 30 min after exercise and analyzed for EV concentration, size, and microRNA content. The size of EVs was similar in CP vs. TD, and exercise had no effect. Individuals with CP had an overall lower concentration (similar to 25%, p < 0.05) of EVs. At baseline, let-7a, let-7b and let-7e were downregulated in individuals with CP compared to TD (p < 0.05), while miR-100 expression was higher, and miR-877 and miR-4433 lower in CP compared to TD after exercise (p < 0.05). Interestingly, miR-486 was upregulated similar to 2-fold in the EVs of CP vs. TD both at baseline and after exercise. We then performed an in silico analysis of miR-486 targets and identified the satellite cell stemness factor Pax7 as a target of miR-486. C2C12 myoblasts were cultured with a miR-486 mimetic and RNA-sequencing was performed. Gene enrichment analysis revealed that several genes involved in sarcomerogenesis and extracellular matrix (ECM) were downregulated. Our data suggest that circulating miR-486 transported by EVs is elevated in individuals with CP and that miR-486 alters the transcriptome of myoblasts affecting both ECM- and sarcomerogenesis-related genes, providing a link to the skeletal muscle alterations observed in individuals with CP., Funding Agencies|Futurum-the Academy for Health and Care, Region Jonkoping County, Sweden; Swedish Kidney Foundation [FUTURUM-937508, 870471]; NIH [F2019-0048]; H.K.H. Kronprinsessan Lovisas foerening foer barnasjukvard [P20GM104320-07]; Swedish Society of Medical Research; Sunnerdahls handikappstiftelse; Norrbacka Eugenia Stiftelsen; career grant from the Swedish National Space Agency; [2021-00159]

PURPOSE: To determine the physiological response and association to peak oxygen uptake of the 6-minute Frame Running test (6-MFRT) in persons with cerebral palsy (CP).METHODS: Twenty-four participants with CP, Gross Motor Function Classification System II/III/IV, performed the 6-MFRT. Distance, peak heart rate (HR peak ), peak respiratory exchange ratio (RER peak ), and peak oxygen uptake ( O 2peak ) were measured.RESULTS: HR peak ranged from 146 to 201 beats per minute, RER peak from 0.94 to 1.49, 6-MFRT distance from 179 to 1220 m and O 2peak from 0.62 to 2.18 L/min. HR peak was achieved in 63%, RER peak in 71%. A strong correlation was observed between 6-MFRT and O 2peak .CONCLUSIONS: The 6-MFRT represented a (near) maximum effort for 75% of the participants and the 6-MFRT can be used to estimate oxygen consumption on an individual basis.

Mitochondrial derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE (n=10, 45 min cycling at 70% of estimated VO2max), RE (n=10, 4 sets x 7RM, leg press and knee extension), or control (CON, n=10). Skeletal muscle biopsies and blood samples were collected before and at 30 minutes and 3 hours following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes (VO2max, leg strength or muscle mitochondrial (mt) DNA copy number). Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN., QC 20211011

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks. RESULTS: The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p<0.05) except complex II. Total peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha) messenger RNA (p<0.004), isoforms PGC1 alpha 1 (p=0.05), and PGC1 alpha 4 (p<0.001) were reduced in CP. Transcriptional similarities were observed between CP, aging, and 90 days' bed rest. INTERPRETATION: Mitochondrial biogenesis, mtDNA, and oxidative phosphorylation protein content are reduced in CP muscle compared with typically developing muscle. Transcriptional pathways shared between aging and long-term unloading suggests metabolic dysregulation in CP, which may guide therapeutic strategies for combatting CP muscle pathology.

Key points Ribosome biogenesis and MYC transcription are associated with acute resistance exercise (RE) and are distinct from endurance exercise in human skeletal muscle throughout a 24 h time course of recovery. A PCR-based method for relative ribosomal DNA (rDNA) copy number estimation was validated by whole genome sequencing and revealed that rDNA dosage is positively correlated with ribosome biogenesis in response to RE. Acute RE modifies rDNA methylation patterns in enhancer, intergenic spacer and non-canonical MYC-associated regions, but not the promoter. Myonuclear-specific rDNA methylation patterns with acute mechanical overload in mice corroborate and expand on rDNA findings with RE in humans. A genetic predisposition for hypertrophic responsiveness may exist based on rDNA gene dosage. Ribosomes are the macromolecular engines of protein synthesis. Skeletal muscle ribosome biogenesis is stimulated by exercise, although the contribution of ribosomal DNA (rDNA) copy number and methylation to exercise-induced rDNA transcription is unclear. To investigate the genetic and epigenetic regulation of ribosome biogenesis with exercise, a time course of skeletal muscle biopsies was obtained from 30 participants (18 men and 12 women; 31 +/- 8 years, 25 +/- 4 kg m(-2)) at rest and 30 min, 3 h, 8 h and 24 h after acute endurance (n = 10, 45 min cycling, 70% V?O2max) or resistance exercise (n = 10, 4 x 7 x 2 exercises); 10 control participants underwent biopsies without exercise. rDNA transcription and dosage were assessed using quantitative PCR and whole genome sequencing. rDNA promoter methylation was investigated using massARRAY EpiTYPER and global rDNA CpG methylation was assessed using reduced-representation bisulphite sequencing. Ribosome biogenesis and MYC transcription were associated primarily with resistance but not endurance exercise, indicating preferential up-regulation during hypertrophic processes. With resistance exercise, ribosome biogenesis was associated, Funding Agencies|Futurum- the Academy forHealth and Care, Region Jonkoping County, Sweden; Swedish Kidney Foundation; Swedish Research Council for Sports; National Institutes of Health grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIH K99 AG063994]

How regular physical activity is able to improve health remains poorly understood. The release of factors from skeletal muscle following exercise has been proposed as a possible mechanism mediating such systemic benefits. We describe a mechanism wherein skeletal muscle, in response to a hypertrophic stimulus induced by mechanical overload (MOV), released extracellular vesicles (EVs) containing muscle-specific miR-1 that were preferentially taken up by epidydimal white adipose tissue (eWAT). In eWAT, miR-1 promoted adrenergic signaling and lipolysis by targeting Tfap2 alpha, a known repressor of Adr beta 3 expression. Inhibiting EV release prevented the MOV-induced increase in eWAT miR-1 abundance and expression of lipolytic genes. Resistance exercise decreased skeletal muscle miR-1 expression with a concomitant increase in plasma EV miR-1 abundance, suggesting a similar mechanism may be operative in humans. Altogether, these findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV-mediated delivery of miR-1., Funding Agencies|National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01DK119619]; Futurum-the Academy for Health and Care, Region Jonkoping County; Swedish Research Council for Sports Science

Objective: To investigate the potential of an acute bout of transcranial magnetic stimulation to induce anabolic signalling. Design: Experimental intervention on healthy subjects. Subjects: Ten healthy subjects, 5 women and 5 men (mean age 32 years; standard deviation (SD) 4). Methods: Transcranial magnetic stimulation, resulting in contraction of the quadriceps muscles, was applied at a frequency of 10 Hz for 10 s followed by 20 s of rest, repeated 40 times over 20 min. Electromyography and force data were collected for all transcranial magnetic stimulation sequences. Muscle biopsies were obtained from the vastus lateralis muscle before and 1 and 3 h after stimulation for evaluation of the molecular response of the muscle. Results: The described stimulation decreased phosphorylation of AKT at Thr308 (1 h: -29%, 3 h: -38%; p<0.05) and mTOR phosphorylation at Ser2448 (1 h: -10%; ns, 3 h: -21%; p < 0.05), both in the anabolic pathway. Phosphorylation of AMPK, ACC and ULK1 were not affected. c-MYC gene expression was unchanged following transcranial magnetic stimulation, but rDNA transcription decreased (1 h: -28%, 3 h: -19%; p<0.05). PGC1 alpha-exlb mRNA increased (1 h: 2.3-fold, 3 h: 2.6-fold; p<0.05), which also correlated with vastus lateralis electromyography activity, while other PGC-1 alpha variants were unchanged. Conclusion: Acute transcranial magnetic stimulation of skeletal muscle in weight-bearing healthy individuals did not induce anabolic signalling, but some signs of impaired muscle anabolism were detected. Therefore, these results do not support the use of acute transcranial magnetic stimulation in preventing muscle wasting., Funding Agencies|Futurum - the Academy for Health and Care, Region Jonkoping County, Sweden; Swedish Society of Medicine