Signaling In Muscle Research Articles

Model-based image reconstruction with wavelet sparsity regularization for through-plane resolution restoration in T2 -weighted spin-echo prostate MRI.

The purpose is to develop a model-based image-reconstruction method using wavelet sparsity regularization for maintaining restoration of through-plane resolution but with improved retention of SNR versus linear reconstruction using Tikhonov (TK) regularization in high through-plane resolution (1 mm) T2 -weighted spin-echo (T2SE) images of the prostate. A wavelet sparsity (WS)-regularized image reconstruction was developed that takes as input a set of ≈80 overlapped 3-mm-thick slices acquired using a T2SE multislice scan and typically 30 coil elements. After testing in contrast and resolution phantoms and calibration in 6 subjects, the WS reconstruction was evaluated in 16 consecutive prostate T2SE MRI exams. Results reconstructed with nominal 1-mm thickness were compared with those from the TK reconstruction with the same raw data. Results were evaluated radiologically. The ratio of magnitude of prostate signal to periprostatic muscle signal was used to assess the presence of noise reduction. Technical performance was also compared with a commercial 3D-T2SE sequence. The new WS reconstruction was assessed as superior statistically to TK for overall SNR, contrast, and multiple evaluation criteria related to sharpness while retaining the high (1 mm) through-plane resolution. Wavelet sparsity tended to provide improved overall diagnostic quality versus TK, but not significantly so. In all 16 studies, the prostate-to-muscle signal ratio increased. Model-based WS-regularized reconstruction consistently provides improved SNR in high (1 mm) through-plane resolution images of prostate T2SE MRI versus linear reconstruction using TK regularization.

Sclerostin aggravates insulin signaling in skeletal muscle and hepatic steatosis via upregulation of ER stress by mTOR-mediated inhibition of autophagy under hyperlipidemic conditions.

Recently, sclerostin (SCL), a circulating glycoprotein, was proposed to be a novel myokine involved in developing metabolic disorders. The association between SCL levels and insulin resistance in skeletal muscle, liver, and adipose tissue was studied in individuals with aggravated glucose tolerance. Thus, we hypothesized that elevated circulating SCL might affect skeletal muscle insulin signaling and hepatic lipid metabolism, and aimed to investigate the effects of SCL on skeletal muscle insulin resistance and hepatic steatosis in obesity using in vitro and in vivo experimental models under hyperlipidemic conditions. In the current study, we found elevated SCL messenger RNA expression levels in myocytes in obese patients. In addition to a higher blood level, SCL was expressed at an elevated level in the skeletal muscle of mice fed a high-fat diet (HFD). Higher SCL release levels and expression were also noticed in palmitate-treated C2C12 myocytes. SCL suppression by in vivo transfection improves skeletal muscle insulin resistance and hepatic steatosis in HFD-fed mice. The treatment of C2C12 myocytes with recombinant SCL aggravated insulin signaling. Furthermore, treatment with SCL augmented lipogenic lipid deposition in human primary hepatocytes. Treatment with SCL upregulated mammalian target of rapamycin (mTOR) phosphorylation and suppressed autophagy markers, thereby causing endoplasmic reticulum (ER) stress. 4-Phenylbutyric acid, a pharmacological ER stress inhibitor, abolished the effects of SCL on insulin signaling in C2C12 myocytes and lipid accumulation in primary hepatocytes. In conclusion, SCL promotes skeletal muscle insulin resistance and hepatic steatosis by upregulating ER stress via the mTOR/autophagy-mediated pathway. The present study suggests that antagonizing SCL might be a novel therapeutic strategy for simultaneously managing insulin resistance and hepatic steatosis in obesity.

Control of Brushless Direct-Current Motors Using Bioelectric EMG Signals.

(1) Background: The purpose of this study was to evaluate the analysis of measurements of bioelectric signals obtained from electromyographic sensors. A system that controls the speed and direction of rotation of a brushless DC motor (BLDC) was developed; (2) Methods: The system was designed and constructed for the acquisition and processing of differential muscle signals. Basic information for the development of the EMG signal processing system was also provided. A controller system implementing the algorithm necessary to control the speed and direction of rotation of the drive rotor was proposed; (3) Results: Using two muscle groups (biceps brachii and triceps), it was possible to control the direction and speed of rotation of the drive unit. The control system changed the rotational speed of the brushless motor with a delay of about 0.5 s in relation to the registered EMG signal amplitude change; (4) Conclusions: The prepared system meets all the design assumptions. In addition, it is scalable and allows users to adjust the signal level. Our designed system can be implemented for rehabilitation, and in exoskeletons or prostheses.

A comparison of contributions of individual muscle and combination muscles to interaction force prediction using KPCA-DRSN model.

Rapid and accurate prediction of interaction force is an effective way to enhance the compliant control performance. However, whether individual muscles or a combination of muscles is more suitable for interaction force prediction under different contraction tasks is of great importance in the compliant control of the wearable assisted robot. In this article, a novel algorithm that is based on sEMG and KPCA-DRSN is proposed to explore the relationship between interaction force prediction and sEMG signals. Furthermore, the contribution of each muscle to the interaction force is assessed based on the predicted results. First of all, the experimental platform for obtaining the sEMG is described. Then, the raw sEMG signal of different muscles is collected from the upper arm during different contractions. Meanwhile, the output force is collected by the force sensor. The Kernel Principal Component Analysis (KPCA) method is adopted to remove the invalid components of the raw sEMG signal. After that, the processed sequence is fed into the Deep Residual Shrinkage Network (DRSN) to predict the interaction force. Finally, based on the prediction results, the contribution of each sEMG signal from different muscles to the interaction force is evaluated by the mean impact value (MIV) indicator. The experimental results demonstrate that our methods can automatically extract the valid features of sEMG signal and provided fast and efficient prediction. In addition, the single muscle with the largest MIV index could predict the interaction force faster and more accurately than the muscle combination in different contraction tasks. The finding of our research provides a solid evidence base for the compliant control of the wearable robot.

Assessing muscle-specific potassium concentrations in human lower leg using potassium magnetic resonance imaging.

Noninvasively assessing tissue potassium concentrations (TPCs) using potassium magnetic resonance imaging (39 K MRI) could give valuable information on physiological processes connected to various pathologies. However, because of inherently low 39 K MR image resolution and strong signal blurring, a reliable measurement of the TPC is challenging. The aim of this work was to investigate the feasibility of a muscle-specific TPC determination with a focus on the influence of a varying residual quadrupolar interaction in human lower leg muscles. The quantification accuracy of a muscle-specific TPC determination was first assessed using simulated 39 K MRI data. In vivo 39 K and corresponding sodium (23 Na) MRI data of healthy lower leg muscles (n = 14, seven females) were acquired on a 7-T MR system using a double-resonant 23 Na/39 K birdcage Tx/Rx RF coil. Additional 1 H MR images were acquired on a 3-T MR system and used for tissue segmentation. Quantification of TPC was performed after a region-based partial volume correction (PVC) using five external reference phantoms. Simulations not only underlined the importance of PVC for correctly assessing muscle-specific TPC values, but also revealed the strong impact of a varying residual quadrupolar interaction between different muscle regions on the measured TPC. Using 39 K T2 * decay curves, we found significantly higher residual quadrupolar interaction in tibialis anterior muscle (TA; ωq = 194 ± 28 Hz) compared with gastrocnemius muscle (medial/lateral head, GM/GL; ωq = 151 ± 25 Hz) and soleus muscle (SOL; ωq = 102 ± 32 Hz). If considered in the PVC, TPC in individual muscles was similar (TPC = 98 ± 11/96 ± 14/99 ± 8/100 ± 12 mM in GM/GL/SOL/TA). Comparison with tissue sodium concentrations suggested that residual quadrupolar interactions might also influence the 23 Na MRI signal of lower leg muscles. A TPC determination of individual lower leg muscles is feasible and can therefore be applied in future studies. Considering a varying residual quadrupolar interaction for PVC of 39 K MRI data is essential to reliably assess potassium concentrations in individual muscles.

Cathelicidin-related antimicrobial peptide mediates skeletal muscle degeneration caused by injury and Duchenne muscular dystrophy in mice.

Cathelicidin, an antimicrobial peptide, plays a key role in regulating bacterial killing and innate immunity; however, its role in skeletal muscle function is unknown. We investigated the potential role of cathelicidin in skeletal muscle pathology resulting from acute injury and Duchenne muscular dystrophy (DMD) in mice. Expression changes and muscular localization of mouse cathelicidin-related antimicrobial peptide (Cramp) were examined in the skeletal muscle of normal mice treated with chemicals (cardiotoxin and BaCl2 ) or in dystrophic muscle of DMD mouse models (mdx, mdx/Utrn+/- and mdx/Utrn-/- ). Cramp penetration into myofibres and effects on muscle damage were studied by treating synthetic peptides to mouse skeletal muscles or C2C12 myotubes. Cramp knockout (KO) mice and mdx/Utrn/Cramp KO lines were used to determine whether Cramp mediates muscle degeneration. Muscle pathophysiology was assessed by histological methods, serum analysis, grip strength and lifespan. Molecular factors targeted by Cramp were identified by the pull-down assay and proteomic analysis. In response to acute muscle injury, Cramp was activated in muscle-infiltrating neutrophils and internalized into myofibres. Cramp treatments of mouse skeletal muscles or C2C12 myotubes resulted in muscle degeneration and myotube damage, respectively. Genetic ablation of Cramp reduced neutrophil infiltration and ameliorated muscle pathology, such as fibre size (P<0.001; n=6) and fibrofatty infiltration (P<0.05). Genetic reduction of Cramp in mdx/Utrn+/- mice not only attenuated muscle damage (35%, P<0.05; n=9-10), myonecrosis (53%, P<0.05), inflammation (37-65%, P<0.01) and fibrosis (14%, P<0.05) but also restored muscle fibre size (14%, P<0.05) and muscle force (18%, P<0.05). Reducing Cramp levels led to a 63% (male, P<0.05; n=10-14) and a 124% (female, P<0.001; n=20) increase in the lifespan of mdx/Utrn-/- mice. Proteomic and mechanistic studies revealed that Cramp cross-talks with Ca2+ signalling in skeletal muscle through sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase1 (SERCA1). Cramp binds and inactivates SERCA1, leading to the activation of Ca2+ -dependent calpain proteases that exacerbate DMD progression. These findings identify Cramp as an immune cell-derived regulator of skeletal muscle degeneration and provide a potential therapeutic target for DMD.

A novel reflex analysis of healthy and spinal cord-injured individuals

Abstract Spinal cord injury (SCI) has a drastic effect on the quality of life of those affected. There is thus a great need for new knowledge that may increase their quality of life. The goal of this research was to develop and set up a measurement system for exact measurements of times between events in a patellar reflex test and a transcutaneous spinal cord stimulation (tSCS) and compare the two in healthy and spinal cord-injured individuals. 21 individuals with a healthy nervous system and 2 spinal cord-injured individuals were subjected to the patellar reflex test and tSCS. The patellar reflex of one individual with a complete SCI at vertebras C6-C7 after an accident was delayed by 24% compared with the healthy subjects, while the reflex time of the other SCI individual, who had cancer in vertebra T3, was shortened by 23%. There was also a difference in the reflex between the patellar reflex test and the tSCS due to action potential conduction distance. In this study, a processing method was created for comparing muscle signals generated by patellar strikes or electrical stimulation to the posterior nerve roots. Data from the subjects with central nervous system lesions showed characteristic differences from reference data.

Androgen Actions in Adipose Tissue, But Not Skeletal Muscle, are Involved in the Development of Metabolic PCOS Features in a Mouse Model

Background: Polycystic ovary syndrome (PCOS) is a common disorder characterised by endocrine, reproductive and metabolic dysfunction. Hyperandrogenism is a key diagnostic trait and evidence supports a role for androgen receptor (AR) mediated actions in PCOS pathogenesis. Aberrant AR signalling in adipose tissue and muscle have been proposed as being involved in PCOS pathogenesis, but their importance and the precise AR signalling mechanisms involved remain undefined. Aim: To investigate the role of AR signalling in white adipose tissue (WAT), brown adipose tissue (BAT) and skeletal muscle in the development of PCOS. Method: WT, global androgen receptor knockout (ARKO) and skeletal muscle-specific (SkMARKO) mice were exposed to DHT to induce PCOS. ARKO (AR−/−) WAT/BAT was transplanted into WT (AR+/+) DHT-induced PCOS females, and WT WAT/BAT was transplanted into ARKO DHT-induced PCOS females. After 12 weeks of DHT exposure all mice were assessed for the presence of reproductive and metabolic PCOS traits. Results: DHT exposure in WT females induced key reproductive and metabolic PCOS traits. SkMARKO mice treated with DHT displayed a similar phenotype to DHT-treated WT females, with full development of reproductive and metabolic PCOS traits. Transplantation of ARKO WAT/BAT into DHT-treated WT females prevented the development of some metabolic PCOS features, as mice exhibited a significantly lower body weight (P&lt;0.05), decreased visceral adiposity (P&lt;0.05), and smaller adipocyte size (P&lt;0.05) compared to DHT-treated WT females with sham surgery. In contrast, reproductive PCOS traits were not ameliorated by WAT or BAT transplantation. Furthermore, DHT exposure in ARKO female mice transplanted with WT WAT/BAT did not lead to the development of PCOS traits. Conclusion: WAT and BAT, but not skeletal muscle, are key sites of AR-mediated actions involved in the development of metabolic PCOS traits. These data support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS.

Signaling and Gene Expression in Skeletal Muscles in Type 2 Diabetes: Current Results and OMICS Perspectives.

Skeletal muscles mainly contribute to the emergence of insulin resistance, impaired glucose tolerance and the development of type 2 diabetes. Molecular mechanisms that regulate glucose uptake are diverse, including the insulin-dependent as most important, and others as also significant. They involve a wide range of proteins that control intracellular traffic and exposure of glucose transporters on the cell surface to create an extensive regulatory network. Here, we highlight advantages of the omics approaches to explore the insulin-regulated proteins and genes in human skeletal muscle with varying degrees of metabolic disorders. We discuss methodological aspects of the assessment of metabolic dysregulation and molecular responses of human skeletal muscle to insulin. The known molecular mechanisms of glucose uptake regulation and the first results of phosphoproteomic and transcriptomic studies are reviewed, which unveiled a large-scale array of insulin targets in muscle cells. They demonstrate that a clear depiction of changes that occur during metabolic dysfunction requires systemic and combined analysis at different levels of regulation, including signaling pathways, transcription factors, and gene expression. Such analysis seems promising to explore yet undescribed regulatory mechanisms of glucose uptake by skeletal muscle and identify the key regulators as potential therapeutic targets.

Non-alcoholic fatty liver disease-related fibrosis and sarcopenia: An altered liver-muscle crosstalk leading to increased mortality risk.

In the last few decades, the loss of skeletal muscle mass and function, known as sarcopenia, has significantly increased in prevalence, becoming a major global public health concern. On the other hand, the prevalence of non-alcoholic fatty liver disease (NAFLD) has also reached pandemic proportions, constituting the leading cause of hepatic fibrosis worldwide. Remarkably, while sarcopenia and NAFLD-related fibrosis are independently associated with all-cause mortality, the combination of both conditions entails a greater risk for all-cause and cardiac-specific mortality.Interestingly, both sarcopenia and NAFLD-related fibrosis share common pathophysiological pathways, including insulin resistance, chronic inflammation, hyperammonemia, alterations in the regulation of myokines, sex hormones and growth hormone/insulin-like growth factor-1 signaling, which may explain reciprocal connections between these two disorders. Additional contributing factors, such as the gut microbiome, may also play a role in this relationship. In skeletal muscle,phosphatidylinositol 3-kinase/Akt and myostatin signaling are the central anabolic and catabolic pathways, respectively, and the imbalance between them can lead to muscle wasting in patients with NAFLD-related fibrosis. In this review, we summarize the bidirectional influence between NAFLD-related fibrosis and sarcopenia, highlighting the main potential mechanisms involved in this complex crosstalk, and we discuss the synergistic effects of both conditions in overall and cardiovascular mortality.

Mineralocorticoid Receptors Mediate Diet-Induced Lipid Infiltration of Skeletal Muscle and Insulin Resistance.

Excess circulating lipids increase total intramyocellular (IMC) lipid content and ectopic fat storage, resulting in lipotoxicity and insulin resistance in skeletal muscle. Consumption of a diet high in fat and refined sugars-a Western diet (WD)-has been shown to activate mineralocorticoid receptors (MRs) and promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study, we investigated the mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic skeletal muscle lipid accumulation and related insulin resistance. Six-week-old C57BL/6J mice were fed either a mouse chow diet or a WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD-induced in vivo glucose intolerance and insulin resistance, and improved soleus insulin metabolic signaling. Improved insulin sensitivity was accompanied by increased glucose transporter 4 (Glut4) expression in conjunction with decreased soleus free fatty acid and IMC lipid content, as well as CD36 expression. Additionally, spironolactone prevented WD-induced soleus mitochondria dysfunction. Furthermore, MR signaling also mediated WD/aldosterone-induced reductions in soleus microRNA (miR)-99a, which was identified to negatively target CD36 and prevented palmitic acid-induced increases in CD36 expression, lipid droplet formation, mitochondria dysfunction, and insulin resistance in C2C12 cells. These data indicate that inhibition of MR activation with spironolactone prevented diet-induced abnormal expression of miR-99a, which had the capacity to reduce CD36, leading to reduced IMC lipid content and improved soleus mitochondria function and insulin sensitivity.

Constitutive activation of estrogen receptor α signaling in muscle prolongs exercise endurance in mice

Estrogen is a female hormone that plays a role in various tissues, although the mechanism in skeletal muscle has not been fully clarified. We previously showed that systemic administration of estrogen for 10 weeks ameliorated decreased exercise endurance in ovariectomized mice. To assess whether a long-term and muscle-specific activation of estrogen signaling modulates muscle function, we constructed an expression plasmid for a constitutively active estrogen receptor α (caERα) under the control of muscle creatine kinase (Mck) gene promoter/enhancer. In C2C12 mouse myoblastic cells, transfection of the Mck-caERα plasmid elevated the estrogen response element-driven transcription in a ligand-independent manner. Using this construct, we generated Mck-caERα transgenic mice, in which caERα is predominantly expressed in muscle. Treadmill running test revealed that female Mck-caERα mice exhibit a prolonged running time and distance compared with the wild-type mice. Moreover, microarray expression analysis revealed that the genes related to lipid metabolism, insulin signaling, and growth factor signaling were particularly upregulated in the quadriceps femoris muscle of Mck-caERα mice. These results suggest that estrogen signaling potentiates exercise endurance in skeletal muscle through modulating the expression of metabolism-associated genes.

The female syndecan-4-/- heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels.

Background: In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4−/− mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle (tibialis anterior, TA) of female syndecan-4−/− mice. To determine if the differences seen in Akt signaling are sex specific, we have presently investigated Akt signaling in the cardiac muscle of sedentary and exercised female syndecan-4−/− mice. To get deeper insight into the female syndecan-4−/− heart, alterations in cardiomyocyte size, a wide variety of different extracellular matrix components, well-known syndecan-4 binding partners and associated signaling pathways have also been investigated. Methods: Left ventricles (LVs) from sedentary and exercise trained female syndecan-4−/− and WT mice were analyzed by immunoblotting and real-time PCR. Cardiomyocyte size and phosphorylated Ser473-Akt were analyzed in isolated adult cardiomyocytes from female syndecan-4−/− and WT mice by confocal imaging. LV and skeletal muscle (TA) from sedentary male syndecan-4−/− and WT mice were immunoblotted with Akt antibodies for comparison. Glucose levels were measured by a glucometer, and fasting blood serum insulin and C-peptide levels were measured by ELISA. Results: Compared to female WT hearts, sedentary female syndecan-4−/− LV cardiomyocytes were smaller and hearts had higher levels of pSer473-Akt and its downstream target pSer9-GSK-3β. The pSer473-Akt inhibitory phosphatase PHLPP1/SCOP was lowered, which may be in response to the elevated serum insulin levels found in the female syndecan-4−/− mice. We also observed lowered levels of pThr308-Akt/Akt and GLUT4 in the female syndecan-4−/− heart and an increased LRP6 level after exercise. Otherwise, few alterations were found. The pThr308-Akt and pSer473-Akt levels were unaltered in the cardiac and skeletal muscles of sedentary male syndecan-4−/− mice. Conclusion: Our data indicate smaller cardiomyocytes, an elevated insulin/pSer473-Akt/pSer9-GSK-3β signaling pathway, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels in the female syndecan-4−/− heart. In contrast, cardiomyocyte size, and Akt signaling were unaltered in both cardiac and skeletal muscles from male syndecan-4−/− mice, suggesting important sex differences.

Effects of high-intensity interval training with hyperbaric oxygen.

Hyperbaric Oxygen (HBO2) has been proposed as a pre-conditioning method to enhance exercise performance. Most prior studies testing this effect have been limited by inadequate methodologies. Its potential efficacy and mechanism of action remain unknown. We hypothesized that HBO2 could enhance aerobic capacity by inducing mitochondrial biogenesis via redox signaling in skeletal muscle. HBO2 was administered in combination with high-intensity interval training (HIIT), a potent redox stimulus known to induce mitochondrial biogenesis. Aerobic capacity was tested during acute hypobaric hypoxia seeking to shift the limiting site of whole body V̇O2 from convection to diffusion, more closely isolating any effect of improved oxidative capacity. Healthy volunteers were screened with sea-level (SL) V̇O2peak testing. Seventeen subjects were enrolled (10 men, 7 women, ages 26.5±1.3 years, BMI 24.6±0.6 kg m−2, V̇O2peak SL = 43.4±2.1). Each completed 6 HIIT sessions over 2 weeks randomized to breathing normobaric air, “HIIT+Air” (PiO2 = 0.21 ATM) or HBO2 (PiO2 = 1.4 ATM) during training, “HIIT+HBO2” group. Training workloads were individualized based on V̇O2peak SL test. Vastus Lateralis (VL) muscle biopsies were performed before and after HIIT in both groups. Baseline and post-training V̇O2peak tests were conducted in a hypobaric chamber at PiO2 = 0.12 ATM. HIIT significantly increased V̇O2peak in both groups: HIIT+HBO2 31.4±1.5 to 35.2±1.2 ml kg−1·min−1 and HIIT+Air 29.0±3.1 to 33.2±2.5 ml kg−1·min−1 (p = 0.005) without an additional effect of HBO2 (p = 0.9 for interaction of HIIT x HBO2). Subjects randomized to HIIT+HBO2 displayed higher skeletal muscle mRNA levels of PPARGC1A, a regulator of mitochondrial biogenesis, and HK2 and SLC2A4, regulators of glucose utilization and storage. All other tested markers of mitochondrial biogenesis showed no additional effect of HBO2 to HIIT. When combined with HIIT, short-term modest HBO2 (1.4 ATA) has does not increase whole-body V̇O2peak during acute hypobaric hypoxia. (ClinicalTrials.gov Identifier: NCT02356900; https://clinicaltrials.gov/ct2/show/NCT02356900).

Effect of losartan treatment on Smad signaling and recovery from hindlimb unloading-induced soleus muscle atrophy in female rats

Losartan, an angiotensin II type 1 receptor blocker, exerts protective effect on soleus muscle atrophy in female rats. Thus, we aimed to examine the effect of losartan treatment on the recovery of atrophied soleus muscles. Female Wistar rats were subjected to hindlimb unloading for 7 d and then reloading for 7 d with either phosphate-buffered saline (PBS; n = 9) or losartan (40 mg/kg/day; n = 9). The soleus muscles were removed at rest (sedentary control [SED]; n = 9), after 7 d of hindlimb unloading (HU; n = 9), and after 7 d of reloading (HUR-PBS or HUR-LOS; n = 9 each). The absolute and relative weights, and fiber cross-sectional area (CSA) of the soleus muscles of rats in the HU group were significantly reduced as compared to those of the rats in the SED group at 7 d post-hindlimb unloading. Seven days of reloading significantly increased the muscle weights of rats in the HUR-PBS and HUR-LOS groups, with the recovery rate of the absolute muscle weight and type I fiber CSA being significantly higher in the HUR-LOS group (6.1% and 10.1%, respectively) than in the HUR-PBS group (4.7% and 5.2%, respectively) (p < 0.05). Moreover, the absolute and relative muscle weight in HUR-PBS were lower than SED; however, no significant difference was observed between the SED and HUR-LOS groups. CSAs of type I and IIa fiber were significantly higher in the HUR-LOS group than in the HU group. Losartan administration during reloading resulted in increased Smad1/5/8 and mTOR signaling and decreased Smad2/3 signaling and protein ubiquitination, facilitating the recovery of atrophied soleus muscle. Therefore, losartan administration-induced muscle recovery may partially be attributed to enhanced Smad1/5/8 and mTOR signaling activation, and reduced activation of canonical TGF-β signaling (Smad2/3) in the soleus muscle.

Nuclear receptors as potential therapeutic targets in peripheral arterial disease and related myopathy.

Peripheral arterial disease (PAD) is a prevalent cardiovascular complication of limb vascular insufficiency, causing ischemic injury, mitochondrial metabolic damage and functional impairment in the skeletal muscle, and ultimately leading to immobility and mortality. While potential therapies have been mostly focussed on revascularization, none of the currently available pharmacological treatments are fully effective in PAD, often leading to amputations, particularly in chronic metabolic diseases. One major limitation of focussed angiogenesis and revascularization as a therapeutic strategy is a limited effect on metabolic restoration and muscle regeneration in the affected limb. Therefore, additional preclinical investigations are needed to discover novel treatment options for PAD preferably targeting multiple aspects of muscle recovery. In this review, we propose nuclear receptors expressed in the skeletal muscle as potential candidates for ischemic muscle repair in PAD. We review classic steroid and orphan receptors that have been reported to be involved in the regulation of paracrine muscle angiogenesis, oxidative metabolism, mitochondrial biogenesis and muscle regeneration, and discuss how these receptors could be critical for recovery from ischemic muscle damage. Furthermore, we identify existing gaps in our understanding of nuclear receptor signalling in the skeletal muscle and propose future areas of research that could be instrumental in exploring nuclear receptors as therapeutic candidates for treating PAD.

What Muscle Signals Mediate the Beneficial Effects of Exercise on Cognition?

Cumulative evidence indicates that physical exercise has positive effects on cognitive functions. Physical activity decreases the rate of cognitive decline both in healthy people and in people with neurodegenerative disorders across the lifespan.1-5 Moderate-to-vigorous physical activity has been shown to be associated with improved learning and memory,1,6,7 executive functions,8 and reaction time.9 A recent longitudinal population-based study including 2,060 cognitively unimpaired men and women aged 70 years or older showed that light-intensity midlife physical activity was associated with less decline in memory function, and vigorous late-life physical activity was associated with less decline in language, attention, and global cognition compared with the no physical activity reference group.10 Physical activity has also been associated with a reduced risk of dementia among individuals with mild cognitive impairment (MCI).11 Aerobic exercise has beneficial effects on cognitive symptoms in Alzheimer disease (AD),12-14 frontotemporal dementia,15 and Parkinson disease (PD).16-19 For example, randomized controlled trials show that physical exercise improved cognition in both AD and MCI groups, with an effect size similar to that of donepezil.20 In patients with PD, aerobic exercise increased functional connectivity of the anterior putamen with the sensorimotor cortex and functional connectivity in the right frontoparietal network, stabilizing disease progression in the corticostriatal sensorimotor network and enhancing cognitive performance.21 Exercise training program also had positive effects on prefrontal activity and gait performance.22

Treadmill Stepping after Epidural Stimulation Cessation in Decerebrated Cats

Summary: It was repeatedly shown that the locomotion evoked by epidural-induced electrical stimulation can last for a certain amount of time after stimulation cessation in decerebrated and spinal animals. This so-called after-stepping reflects the maintenance level for the activation of locomotor neuronal circuitry, but only scarce information exists about after-stepping peculiarities. We provide a comparative investigation of after-stepping and stepping under epidural stimulation using electromyographic and kinematic signals as well as ground reaction forces in 16 decerebrated cats. Our principal findings are as follows: (1) the ground reaction forces decrease more after epidural stimulation cessation compared to anterior–posterior limb movements; (2) the step cycle duration is longer for after-steps; (3) the electromyographic signal of the extensor gastrocnemius lateralis muscle during after-stepping decreases faster compared to the signal from the flexors iliopsoas and tibialis anterior and to the extensor soleus muscle; and (4) electromyographic stability is reduced after epidural stimulation cessation. We suppose that different levels of the spinal central pattern generator can be differently attenuated after external trigger cessation. These data could be important for the elaboration of locomotor models and for rehabilitation techniques. New Findings: Our new findings come from comparative investigations of the so-called after-stepping (locomotion after electrical stimulation cessation) and locomotion observed during epidural-induced electrical stimulation. Our new findings are as follows: after epidural stimulation cessation, (1) the ground reaction forces decrease faster compared to anterior–posterior limb movements; (2) the electromyographic signal of the extensor gastrocnemius lateralis muscle decreases faster compared to the signals from the flexors iliopsoas and tibialis anterior and to the extensor soleus muscle; and (3) electromyographic stability is reduced.

PD 102807 Induces M3 mAChR-Dependent GRK-/Arrestin-Biased Signaling in Airway Smooth Muscle Cells.

G protein-coupled receptors (GPCRs) not only are turned on or off to control canonical G protein signaling but also may be fine-tuned to promote qualitative/biased signaling. Qualitative signaling by M3 muscarinic acetylcholine receptors (mAChRs) has been proposed, but its impact on physiologic systems remains unclear, and currently no biased M3 mAChR ligands have been described. Herein, we identify PD 102807 as a biased M3 ligand and delineate its signaling and function in human airway smooth muscle (ASM) cells. PD 102807 induced M3-mediated β-arrestin recruitment but not calcium mobilization. PD 102807 inhibited methacholine (MCh)-induced calcium mobilization in (M3-expressing) ASM cells. PD 102807 induced phosphorylation of AMP-activated protein kinase (AMPK) and the downstream effector acetyl-coenzyme A carboxylase (ACC). PD 102807- induced phosphorylated (p)-AMPK levels were greatly reduced in ASM cells with minimal M3 expression and were not inhibited by the Gq inhibitor YM-254890. Induction of p-AMPK and p-ACC was inhibited by β-arrestin 1 or GRK2/3 knockdown. Similarly, MCh induced phosphorylation of AMPK/ACC, but these effects were Gq dependent and unaffected by GRK2/3 knockdown. Consistent with the known ability of AMPK to inhibit transforming growth factor β (TGF-β)-mediated functions, PD 102807 inhibited TGF-β-induced SMAD-Luc activity, sm-α-actin expression, actin stress fiber formation, and ASM cell hypercontractility. These findings reveal that PD 102807 is a biased M3 ligand that inhibits M3-transduced Gq signaling but promotes Gq protein-independent, GRK-/arrestin-dependent, M3-mediated AMPK signaling, which in turn regulates ASM phenotype and contractile function. Consequently, biased M3 ligands hold significant promise as therapeutic agents capable of exploiting the pleiotropic nature of M3 signaling.

Resolvin D3 improves the impairment of insulin signaling in skeletal muscle and nonalcoholic fatty liver disease through AMPK/autophagy-associated attenuation of ER stress

Resolvin D3 (RD3), an endogenous lipid mediator derived from omega-3 fatty acids, has been documented to attenuate inflammation in various disease models. Although it has been reported that omega-3 fatty acids attenuate metabolic disorders, the roles of RD3 in insulin signaling in skeletal muscle and hepatic lipid metabolism remain unclear. In the current study, we examined the role of RD3 in skeletal muscle insulin resistance and hepatic steatosis using in vitro and in vivo obesity models. In mouse primary hepatocytes, RD3 treatment reduced lipid accumulation and the production of lipogenic proteins (processed SREBP1 and SCD1) while improving insulin signaling in C2C12 myocytes. Furthermore, RD3 treatment ameliorated palmitate-induced ER stress markers (phospho-eIF2α and CHOP) in mouse primary hepatocytes and C2C12 myocytes. Treatment with RD3 increased phospho-AMPK expression and autophagy markers (LC3 conversion, p62 degradation, and autophagosome formation). AMPK siRNA or 3-MA reduced the effects of RD3 on C2C12 myocytes and mouse primary hepatocytes treated with palmitate. Finally, we confirmed the therapeutic effects of RD3 on skeletal muscle insulin resistance and hepatic lipid metabolism in high-fat diet (HFD)-fed mice. In vivo transfection-mediated suppression of AMPK restored all these changes in animal models. The results of the present study suggest that RD3 alleviates insulin resistance in skeletal muscle and hepatic steatosis via AMPK/autophagy signaling and provides an effective and safe therapeutic approach for treating metabolic disorders, including insulin resistance, type 2 diabetes, and NAFLD.