Signaling In Muscle Research Articles

Sex differences in cachexia outcomes, anabolic signalling and BCAA metabolism following chemotherapy

Sex is a risk factor for cancer. Affecting nearly 80% of cancer patients is cachexia, a body and skeletal muscle-wasting syndrome. Poor nutritional status, tumour related factors and chemotherapy contribute to cachexia. Although negative effects of chemotherapy on skeletal muscle are documented, the majority of studies are completed in male animals. Although the branched-chain amino acids (BCAA: leucine, isoleucine and valine) activate anabolic signalling in skeletal muscle and have been shown to reduce some of the effects of cachexia, BCAA nutritional support does not reverse cachexia and few studies have investigated the effects of chemotherapy on BCAA metabolism in skeletal muscle. Therefore, the objective of this study is to compare the effects of chemotherapy on cachexia outcomes and BCAA metabolism between male and female mice. Three-month-old CD2F1 male and female mice were treated with either the chemotherapy drug cocktail folfiri (50mg/kg 5-fluorouracil (5FU), 90mg/kg Leucovorin and 24mg/kg CPT11) (drug) or vehicle (10% DMSO in saline) for 6-weeks. Within sex, drug treatment led to reductions in body and skeletal muscle weights. Between sex, drug-treated female mice lost more body and gastrocnemius muscle weight compared to drug-treated males. Within sex, drug treated animals exhibited reductions in anabolic signalling, specifically AKT, S6K1, S6 and 4E-BP1. Between sex, drug-treated females mice showed greater loss of anabolic signalling compared to drug-treated males. Within sex, the drug cocktail reduced amino acid transporters SNAT1 and LAT1, while reducing BCAA concentrations in the skeletal muscle. Drug-treated female mice exhibited greater loss of LAT1 compared to male-drug treated mice. However, male-drug treated mice had greater decreases in BCAA concentrations compared to female drug-treated mice. In addition, minimal differences were found within sex for key enzymes involved in BCAA metabolism. However, the inhibitory phosphorylation of branched-chain alpha-ketoacid dehydrogenase complex (BCKD) was elevated only in drug-treated male animals. Lastly, within sex, drug treatment showed elevated levels of BCAA concentrations in the liver, but only male drug-treated mice showed elevated plasma BCAAs compared to male vehicle-treated mice. Our data suggests a link between muscle atrophy and decreased BCAA metabolism during chemotherapy. We found that drug-treated female mice had worsened outcomes for cachexia measures such as body, skeletal muscle weight and anabolic signalling compared to drug-treated male mice. However, drug-treated males exhibited greater decreases in BCAA concentrations and their metabolism compared to drug-treated females. Findings from this study suggest that altered availability and metabolism of the BCAAs may contribute to muscle wasting differently in males and females during chemotherapy and interventions that correct such alterations may need to consider sex in order to better manage cachexia. Nserc, York University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The asymmetrical ESR1 signaling in muscle progenitor cells determines the progression of adolescent idiopathic scoliosis

Adolescent Idiopathic Scoliosis (AIS) is a common pediatric skeletal disease highly occurred in females. The pathogenesis of AIS has not been fully elucidated. Here, we reveal that ESR1 (Estrogen Receptor 1) expression declines in muscle stem/progenitor cells at the concave side of AIS patients. Furthermore, ESR1 is required for muscle stem/progenitor cell differentiation and disrupted ESR1 signaling leads to differentiation defects. The imbalance of ESR1 signaling in the para-spinal muscles induces scoliosis in mice, while reactivation of ESR1 signaling at the concave side by an FDA approved drug Raloxifene alleviates the curve progression. This work reveals that the asymmetric inactivation of ESR1 signaling is one of the causes of AIS. Reactivation of ESR1 signaling in para-spinal muscle by Raloxifene at the concave side could be a new strategy to treat AIS.

Classification of tracheal stenosis with asymmetric misclassification errors from EMG signals using an adaptive cost-sensitive learning method

Upper airway obstruction is characterized by loss of normal airway architecture resulting from various disorders such as infections and asthma. Early detection of airway obstruction is essential to prevent medical deterioration. The objective of this study was to non-invasively identify early-stage tracheal stenosis, using electromyography (EMG) signals of inspiratory muscles. The identification of tracheal stenosis has been defined as an asymmetric misclassification cost problem. Specifically, the EMG signals are used as input to a ResNet-like architecture for tabular data with an Adaptive Cost-Sensitive Learning (AdaCSL) algorithm. The electrical activity of the external intercostal muscle of four healthy individuals was recorded while they breathed through two different tubes, one simulating a narrowed airway and the other simulating a normal airway. Two experiment settings were designed. The first setting aimed to classify tracheal stenosis in a specific subject by training the model on data from other subjects, reflecting the case of diagnosing a new subject. To overcome multi-subject variations, the second setting aimed to classify tracheal stenosis by mixing all subjects’ training and test data. The ResNet-like architecture with an AdaCSL algorithm was significantly better in the first experiment setting with costs that were 43%, 48%, and 59% lower than the cost of the second-best alternative for three different misclassification cost values. It also achieved a lower cost in the second experiment setting over other classifiers. The experiments emphasize the capability of using inspiratory muscle EMG signals to diagnose respiratory disease and demonstrate the usefulness of the AdaCSL algorithm for personalized monitoring.

Exploring the effects of body weight support systems on lower limb kinematics and muscle characteristics

Bipedal gait is one of the most important forms of human movement. However, every year many people lose their ability to walk due to disease. Weight support systems that reduce or even eliminate the effect of upper body mass loading on the lower limbs are among the most commonly used devices in gait rehabilitation. The designed weight support system provides body support while innovatively proposing a torso motion assist function. In this paper, walking experiments were performed on normal healthy subjects under five different weight-supported conditions, and motor and surface electromyography (sEMG) signals of the lower limb muscles were collected and analyzed. The results showed a slight decrease in joint motion of the lower extremities in the reference (free walking) and weight-supported-only assisted conditions, while there was no change in the joint angle curve waveform. In contrast, there was a significant change in the joint angle waveform between weight support plus trunk transfer and free walking. Different muscles differ in the significance of feature changes under different auxiliary conditions. By studying the changes in motor and muscle activation levels in the human lower extremity under the weight support system, it can be used as an indicator to assess specific gait indicators and muscle activity during the rehabilitation of the lower extremity in rehabilitated patients.

Linear spectrum and non-linear complexity features of lumbar muscle surface electromyography between people with and without non-specific chronic low back pain during Biering-Sorensen test.

This study aimed to investigate the electromyographic parameters of lumbar muscles during the Biering-Sorensen test (BST) in people with and without non-specific chronic low back pain (NCLBP). Thirteen healthy controls and thirteen NCLBP patients participated in the current study, where they performed the 90s-BST, while the surface electromyography (sEMG) was recorded from the erector spinae (ES) at L1 and L3 level and lumbar multifidus (LM) at L5 level, bilaterally. Spectral and nonlinear analyses were applied by calculating mean power frequency (MPF), fractal dimension (FD) and the percentage of determinism (%DET) in the 10-second non-overlapping time-windows and EMG-EMG coherence during the first half and second half of the BST. Also, the slopes of the linear fitting curves of MPF, FD and %DET were calculated. NCLBP group had significantly lower rates of changes in MPF, FD and %DET compared to asymptomatic controls in the ES(L3) and LM. Coherence in left-right LM and in the right ES-LM increased significantly in the gamma band in the Control group with no increase in the NCLBP group. Our findings indicated that compared to people with NCLBP, the sEMG signals of lumbar muscles of people without NCLBP were more regular and less complex during the 90s-BST.

Automated Eye Movement Classification Based on EMG of EOM Signals Using FBSE-EWT Technique

The accurate automated eye movement classification is gaining importance in the field of human–computer interaction (HCI). The present article aims at the classification of six types of eye movements from electromyogram (EMG) of extraocular muscles (EOM) signals using the Fourier–Bessel series expansion-based empirical wavelet transform (FBSE-EWT) with time and frequency-domain (TAFD) features. The FBSE-EWT of EMG signals results in Fourier–Bessel intrinsic mode functions (FBIMFs), which correspond to the frequency contents in the signal. A hybrid approach is used to select the prominent FBIMFs followed by the statistical and signal complexity-based feature extraction. Furthermore, metaheuristic optimization algorithms are employed to reduce the feature space dimension. The discrimination ability of the reduced feature set is verified by Kruskal–Wallis statistical test. Multiclass support vector machine (MSVM) has been employed for classification. First, the classification has been performed with TAFD features followed by the combination of TAFD and FBSE-EWT-based reduced feature set. The combination of TAFD and FBSE-EWT-based feature set has provided good classification performance. This study demonstrates the efficacy of FBSE-EWT and subsequent metaheuristic feature selection algorithms in classifying the eye movements from EMG of EOM signals. The combination of TAFD and the selected features through salp swarm optimization algorithm has provided maximum classification accuracy of 98.91% with MSVM employing Gaussian and radial basis function kernels. Thus, the proposed approach has the potential to be used in HCI applications involving biomedical signals.

Defective BVES-mediated feedback control of cAMP in muscular dystrophy

Biological processes incorporate feedback mechanisms to enable positive and/or negative regulation. cAMP is an important second messenger involved in many aspects of muscle biology. However, the feedback mechanisms for the cAMP signaling control in skeletal muscle are largely unknown. Here we show that blood vessel epicardial substance (BVES) is a negative regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling involved in maintaining muscle mass and function. BVES deletion in mice reduces muscle mass and impairs muscle performance, whereas virally delivered BVES expressed in Bves-deficient skeletal muscle reverses these defects. BVES interacts with and negatively regulates ADCY9’s activity. Disruption of BVES-mediated control of cAMP signaling leads to an increased protein kinase A (PKA) signaling cascade, thereby promoting FoxO-mediated ubiquitin proteasome degradation and autophagy initiation. Our study reveals that BVES functions as a negative feedback regulator of ADCY9-cAMP signaling in skeletal muscle, playing an important role in maintaining muscle homeostasis.

Insulin signaling in skeletal muscle during inflammation and/or immobilisation

BackgroundThe decline in the downstream signal transduction pathway of anabolic hormone, insulin, could play a key role in the muscle atrophy and insulin resistance observed in patients with intensive care unit acquired weakness (ICUAW). This study investigated the impact of immobilisation via surgical knee and ankle fixation and inflammation via Corynebacterium parvum injection, alone and in combination, as risk factors for altering insulin transduction and, therefore, their role in ICUAW.ResultsMuscle weight was significantly decreased due to immobilisation [estimated effect size (95% CI) − 0.10 g (− 0.12 to − 0.08); p < 0.001] or inflammation [estimated effect size (95% CI) − 0.11 g (− 0.13 to − 0.09); p < 0.001] with an additive effect of both combined (p = 0.024). pAkt was only detectable after insulin stimulation [estimated effect size (95% CI) 85.1-fold (76.2 to 94.0); p < 0.001] irrespective of the group and phosphorylation was not impaired by the different perturbations. Nevertheless, the phosphorylation of GSK3 observed in the control group after insulin stimulation was decreased in the immobilisation [estimated effect size (95% CI) − 40.2 (− 45.6 to − 34.8)] and inflammation [estimated effect size (95% CI) − 55.0 (− 60.4 to − 49.5)] groups. The expression of phosphorylated GS (pGS) was decreased after insulin stimulation in the control group and significantly increased in the immobilisation [estimated effect size (95% CI) 70.6-fold (58.8 to 82.4)] and inflammation [estimated effect size (95% CI) 96.7 (85.0 to 108.5)] groups.ConclusionsBoth immobilisation and inflammation significantly induce insulin resistance, i.e., impair the insulin signaling pathway downstream of Akt causing insufficient GSK phosphorylation and, therefore, its activation which caused increased glycogen synthase phosphorylation, which could contribute to muscle atrophy of immobilisation and inflammation.

White-skinned sweet potato (Ipomoea batatas L.) acutely suppresses postprandial blood glucose elevation by improving insulin sensitivity in normal rats

Long-term administration of Ipomoea batatas L. (white-skinned sweet potato, WSSP) has been reported to help manage type 2 diabetes mellitus (T2DM) in humans and animals; however, the mechanisms of blood glucose regulation by WSSP remain unclear. Therefore, we aimed to investigate the acute effects of WSSP on blood glucose homeostasis under normal conditions and the underlying mechanisms. Three fractions of WSSP (≤10, 10–50, and >50 kDa) were obtained via ultracentrifugation. Rats were subjected to an oral glucose tolerance test (OGTT) after a single administration of WSSP. The insulin tolerance test (ITT) and pyruvate tolerance test (PTT) were performed to evaluate insulin sensitivity and gluconeogenesis, respectively. Single WSSP administration markedly reduced blood glucose levels as revealed by the OGTT. Serum insulin levels were not increased by WSSP treatment. Blood glucose levels during ITT were significantly reduced due to WSSP treatment. WSSP treatment activated the phosphorylation of Akt, thereby activating insulin signaling in the skeletal muscles and liver. The ≤10 kDa fraction considerably reduced blood glucose levels per the OGTT and ITT. In contrast, gluconeogenesis in PTT and the expression of key enzymes in hepatocytes were suppressed by the >50 kDa fraction. This study demonstrated that WSSP acutely reduced postprandial blood glucose levels by improving insulin sensitivity in skeletal muscles in normal rats, which was attributed to constituents with a molecular weight of ≤10 kDa. Moreover, WSSP treatment suppressed gluconeogenesis in the liver, for which constituents of >50 kDa were responsible. Thus, WSSP can acutely regulate blood glucose homeostasis via multiple mechanisms. Since postprandial hyperglycemia leads to the onset of T2DM, WSSP, as a functional food, may possess potential active compounds that prevent T2DM.

Fine particulate matter (PM2.5)-induced pulmonary oxidative stress contributes to increases in glucose intolerance and insulin resistance in a mouse model of circadian dyssynchrony

Results of human and animal studies independently suggest that either ambient fine particulate matter (PM2.5) air pollution exposure or a disturbed circadian rhythm (circadian dyssynchrony) are important contributing factors to the rapidly evolving type-2-diabetes (T2D) epidemic. The objective of this study is to investigate whether circadian dyssynchrony increases the susceptibility to PM2.5 and how PM2.5 affects metabolic health in circadian dyssynchrony. We examined systemic and organ-specific changes in glucose homeostasis and insulin sensitivity in mice maintained on a regular (12/12 h light/dark) or disrupted (18/6 h light/dark, light-induced circadian dyssynchrony, LICD) light cycle exposed to air or concentrated PM2.5 (CAP, 6 h/day, 30 days). Exposures during Zeitgeber ZT3–9 or ZT11–17 (Zeitgeber in circadian time, ZT0 = begin of light cycle) tested for time-of-day PM2.5 sensitivity (chronotoxicity). Mice transgenic for lung-specific overexpression of extracellular superoxide dismutase (ecSOD-Tg) were used to assess the contribution of CAP-induced pulmonary oxidative stress. Both, CAP exposure from ZT3–9 or ZT11–17, decreased glucose tolerance and insulin sensitivity in male mice with LICD, but not in female mice or in mice kept on a regular light cycle. Although changes in glucose homeostasis in CAP-exposed male mice with LICD were not associated with obesity, they were accompanied by white adipose tissue (WAT) inflammation, impaired insulin signaling in skeletal muscle and liver, and systemic and pulmonary oxidative stress. Preventing CAP-induced oxidative stress in the lungs mitigated the CAP-induced decrease in glucose tolerance and insulin sensitivity in LICD. Our results demonstrate that circadian dyssynchrony is a novel susceptibility state for PM2.5 and suggest that PM2.5 by inducing pulmonary oxidative stress increases glucose intolerance and insulin resistance in circadian dyssynchrony.

Mirror movements – A simple algorithm for mirror activity signal processing and normative values

Mirror activity is an involuntary activation of a muscle when the respective contralateral muscle is contracting. This phenomenon has been described primarily in children and in disease states, and, more recently, also in healthy adults. Different ways of assessing mirror activity have been described.In this work we propose a simple protocol for quantifying the amount of mirror activity during a brief isolated full force isometric contraction of a given muscle. The signal was analyzed by a custom-built algorithm that detects the beginning and the end of muscle contraction. The amount of EMG signal on the mirror muscle in relation to the amount of EMG signal of the active muscle is then calculated.We studied 57 right-handed healthy subjects. Mirror activity was evaluated in the Abductor digiti minimi (ADM) and Tibialis anterior (TA) muscles during a 2–3 s full force isometric contraction. The intensity of mirror movement was represented as a percentage of the signal from maximal voluntary contraction.The performance of the algorithm for the detection of the beginning of muscle contraction was very good, when compared to 2 human operators. Intraclass correlation coefficient was excellent (0.998). The Bland-Altman plots showed similar performances of the algorithm and the human operators.We found a significant correlation of mirror activity with intensity and age. There was significantly more intense mirror activity in the left limbs (non-dominant) when compared to the right limbs.The upper limits of normality for mirror EMG signal was 27.4% for right ADM, 15.4% for left ADM, 10.4% for right TA and 2.1% for left TA.This simple protocol allows for an objective measurement of the amount of mirror activity. We propose this technique for investigation of neurological disorders.

Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant.

Background: Sheldon-Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes). Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis. Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype. Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.

Classification of muscle activity patterns in healthy children using biclustering algorithm

In recent years, there has been major interest in recognising electromyography (EMG) patterns. This work proposes a new method based on a biclustering algorithm which can group strides showing homogeneous EMG activation intervals. The surface EMG signals of biceps femoris, rectus femoris, semitendinosus, lateral gastrocnemius, and medial gastrocnemius muscles of 17 healthy children aged between 4 and 11 years old were obtained using a Trigno EMG wireless system. The data set was tested for different values of parameter α (the threshold describing when the multiple node deletion step is used) and δ (the threshold that limits the value of the mean square residue). The highest number of coincidences of muscle activation was observed in 6 to 7-year-old subjects. This was not affected by their anthropometrics or gender. The obtained biclusters reflect actual differences between the subjects' gait parameters, namely stride length, stride time, and walking speed. These results can be used to develop strategies for finding homogeneous groups of patients.

In Vivo MRI Tracking of Degradable Polyurethane Hydrogel Degradation In Situ Using a Manganese Porphyrin Contrast Agent.

A noninvasive method to track implanted biomaterials is desirable for real-time monitoring of material interactions with host tissues and assessment of efficacy and safety. To explore quantitative in vivo tracking of polyurethane implants using a manganese porphyrin (MnP) contrast agent containing a covalent binding site for pairing to polymers. Prospective, longitudinal. Rodent model of dorsal subcutaneous implants (10 female Sprague Dawley rats). A 3-T; two-dimensional (2D) T1-weighted spin-echo (SE), T2-weighted turbo SE, three-dimensional (3D) spoiled gradient-echo T1 mapping with variable flip angles. A new MnP-vinyl contrast agent to covalently label polyurethane hydrogels was synthesized and chemically characterized. Stability of binding was assessed in vitro. MRI was performed in vitro on unlabeled hydrogels and hydrogels labeled at different concentrations, and in vivo on rats with unlabeled and labeled hydrogels implanted dorsally. In vivo MRI was performed at 1, 3, 5, and 7 weeks postimplantation. Implants were easily identified on T1-weighted SE, and fluid accumulation from inflammation was distinguished on T2-weighted turbo SE. Implants were segmented on contiguous T1-weighted SPGR slices using a threshold of 1.8 times the background muscle signal intensity; implant volume and mean T1 values were then calculated at each timepoint. Histopathology was performed on implants in the same plane as MRI and compared to imaging results. Unpaired t-tests and one-way analysis of variance (ANOVA) were used for comparisons. A P value <0.05 was considered to be statistically significant. Hydrogel labeling with MnP resulted in a significant T1 reduction in vitro (T1=517 ± 36 msec vs. 879 ± 147 msec unlabeled). Mean T1 values of labeled implants in rats increased significantly by 23% over time, from 1 to 7 weeks postimplantation (651 ± 49 msec to 801 ± 72 msec), indicating decreasing implant density. Polymer-binding MnP enables in vivo tracking of vinyl-group coupling polymers. 1. Stage 1.

Ependymal polarity defects coupled with disorganized ciliary beating drive abnormal cerebrospinal fluid flow and spine curvature in zebrafish.

Idiopathic scoliosis (IS) is the most common spinal deformity diagnosed in childhood or early adolescence, while the underlying pathogenesis of this serious condition remains largely unknown. Here, we report zebrafish ccdc57 mutants exhibiting scoliosis during late development, similar to that observed in human adolescent idiopathic scoliosis (AIS). Zebrafish ccdc57 mutants developed hydrocephalus due to cerebrospinal fluid (CSF) flow defects caused by uncoordinated cilia beating in ependymal cells. Mechanistically, Ccdc57 localizes to ciliary basal bodies and controls the planar polarity of ependymal cells through regulating the organization of microtubule networks and proper positioning of basal bodies. Interestingly, ependymal cell polarity defects were first observed in ccdc57 mutants at approximately 17 days postfertilization, the same time when scoliosis became apparent and prior to multiciliated ependymal cell maturation. We further showed that mutant spinal cord exhibited altered expression pattern of the Urotensin neuropeptides, in consistent with the curvature of the spine. Strikingly, human IS patients also displayed abnormal Urotensin signaling in paraspinal muscles. Altogether, our data suggest that ependymal polarity defects are one of the earliest sign of scoliosis in zebrafish and disclose the essential and conserved roles of Urotensin signaling during scoliosis progression.

The test-retest reproducibility of the multiple array probe Leiden in men with lower urinary tract symptoms.

We aimed to study the test-retest reliability of the Multiple Array Probe Leiden (MAPLe), a multiple electrode probe designed to acquire and discriminate electromyography signals in the pelvic floor muscles, in men with lower urinary tract symptoms (LUTS). Adult male patients with LUTS with sufficient knowledge of Dutch language, but without complications (e.g., urinary tract infection), or previous urologic cancer and/or urologic surgery were enrolled. In the initial study, next to physical examination and uroflowmetry, all men underwent MAPLe assessment at baseline and after 6 weeks. Second, participants were reinvited for a new assessment using a stricter protocol. A time interval of 2 h (M2) and 1 week (M3) after baseline (M1) allowed the calculation of the intraday agreement (M1 vs. M2), and the interday agreement (M1 vs. M3) for all 13 MAPLe variables. The outcomes of the initial study in 21 men suggested a poor test-retest reliability. The second study in 23 men showed a good test-retest reliability with intraclass correlations ranging from 0.61 (0.12-0.86) to 0.91 (0.81-0.96). The agreement was generally higher for the intraday determinations than for the interday determinations. This study revealed a good test-retest reliability of the MAPLe device in men with LUTS, when using a strict protocol. With a less strict protocol, the test-retest reliability of MAPLe was poor in this sample. To make valid interpretations of this device in a clinical or research setting, a strict protocol is needed.

Printed soft skin electrodes for seamless bio-impedance measurements

Bio-impedance measurements are widely used to assess various physiological parameters. Contemporary skin electrodes for bio-impedance measurements are cumbersome and novel electrode designs are needed to allow fast and easy placement, long-term stability and user comfort. This investigation introduces dry, printed, bio-compatible electrode arrays, made of screen-printed carbon and inkjet-printed PEDOT:PSS that measure bio-impedance non-invasively and stably. Two contact impedance measurements yield the lowest normalized values of soft electrodes reported to date. Four contact bio-impedance measurements from the radial, ulnar, common carotid and superficial temporal arteries were performed, demonstrating the ability to capture blood pulsation in different areas with small form factor. Owing to the unique properties of the printed electrodes reported here, we were able to demonstrate for the first time blood pulsation in the face, continuous blood pulsation measurement during simultaneous muscle activation and signal stability over many hours.

IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-β) and TGF-β receptor II (TGF-βr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-β signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-βr2 deleted in skeletal muscle (SM TGF-βr2−/−) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-β signaling activator, this study further revealed an essential role of intrinsic TGF-β signaling in regulating muscle cell to express inflammation-related molecules including H-2Kb, H2-Eα, TLR3, and special myokines. TGF-β signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-β signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR–IRE1α–p38 MAPK pathway.

Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.

Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.NEW & NOTEWORTHY Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.

Changes in the Mechanical Properties of Fast and Slow Skeletal Muscle after 7 and 21 Days of Restricted Activity in Rats.

Disuse muscle atrophy is usually accompanied by changes in skeletal muscle structure, signaling, and contractile potential. Different models of muscle unloading can provide valuable information, but the protocols of experiments with complete immobilization are not physiologically representative of a sedentary lifestyle, which is highly prevalent among humans now. In the current study, we investigated the potential effects of restricted activity on the mechanical characteristics of rat postural (soleus) and locomotor (extensor digitorum longus, EDL) muscles. The restricted-activity rats were kept in small Plexiglas cages (17.0 × 9.6 × 13.0 cm) for 7 and 21 days. After this, soleus and EDL muscles were collected for ex vivo mechanical measurements and biochemical analysis. We demonstrated that while a 21-day movement restriction affected the weight of both muscles, in soleus muscle we observed a greater decrease. The maximum isometric force and passive tension in both muscles also significantly changed after 21 days of movement restriction, along with a decrease in the level of collagen 1 and 3 mRNA expression. Furthermore, the collagen content itself changed only in soleus after 7 and 21 days of movement restriction. With regard to cytoskeletal proteins, in our experiment we observed a significant decrease in telethonin in soleus, and a similar decrease in desmin and telethonin in EDL. We also observed a shift towards fast-type myosin heavy chain expression in soleus, but not in EDL. In summary, in this study we showed that movement restriction leads to profound specific changes in the mechanical properties of fast and slow skeletal muscles. Future studies may include evaluation of signaling mechanisms regulating the synthesis, degradation, and mRNA expression of the extracellular matrix and scaffold proteins of myofibers.