Development Of Muscle Atrophy Research Articles

High expression of transcription factor EGR1 is associated with postoperative muscle atrophy in patients with knee osteoarthritis undergoing total knee arthroplasty

BackgroundMuscle atrophy is a typical affliction in patients affected by knee Osteoarthritis (KOA). This study aimed to examine the potential pathogenesis and biomarkers that coalesce to induce muscle atrophy, primarily through the utilization of bioinformatics analysis.MethodsTwo distinct public datasets of osteoarthritis and muscle atrophy (GSE82107 and GSE205431) were subjected to differential gene expression analysis and gene set enrichment analysis (GSEA) to probe for common differentially expressed genes (DEGs) and conduct transcription factor (TF) enrichment analysis from such genes. Venn diagrams were used to identify the target TF, followed by the construction of a protein-protein interaction (PPI) network of the common DEGs governed by the target TF. Hub genes were determined through the CytoHubba plug-in whilst their biological functions were assessed using GSEA analysis in the GTEx database. To validate the study, reverse transcriptase real-time quantitative polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and Flow Cytometry techniques were employed.ResultsA total of 138 common DEGs of osteoarthritis and muscle atrophy were identified, with 16 TFs exhibiting notable expression patterns in both datasets. Venn diagram analysis identified early growth response gene-1 (EGR1) as the target TF, enriched in critical pathways such as epithelial mesenchymal transition, tumor necrosis factor-alpha signaling NF-κB, and inflammatory response. PPI analysis revealed five hub genes, including EGR1, FOS, FOSB, KLF2, and JUNB. The reliability of EGR1 was confirmed by validation testing, corroborating bioinformatics analysis trends.ConclusionsEGR1, FOS, FOSB, KLF2, and JUNB are intricately involved in muscle atrophy development. High EGR1 expression directly regulated these hub genes, significantly influencing postoperative muscle atrophy progression in KOA patients.

Muscle-enriched microRNA-486-mediated regulation of muscular atrophy and exercise.

The objectives of this review were to understand the impact of microRNA-486 on myogenesis and muscle atrophy, and the change of microRNA-486 following exercise, and provide valuable information for improving muscle atrophy based on exercise intervention targeting microRNA-486. Muscle-enriched microRNAs (miRNAs), also referred to as myomiRs, control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli such as exercise. MicroRNA-486 is a miRNA in which a stem-loop sequence is embedded within the ANKYRIN1 (ANK1) locus and is strictly conserved across mammals. MicroRNA-486 is involved in the development of muscle atrophy caused by aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. PI3K/AKT signaling is a positive pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. MicroRNA-486 can activate this pathway by inhibiting phosphatase and tensin homolog (PTEN), it may also indirectly inhibit the HIPPO signaling pathway to promote cell growth. Exercises regulate microRNA-486 expression both in blood and muscle. This review focused on the recent elucidation of sarcopenia regulation by microRNA-486 and its effects on pathological states, including primary muscular disease, secondary muscular disorders, and age-related sarcopenia. Additionally, the role of exercise in regulating skeletal muscle-enriched microRNA-486 was highlighted, along with its physiological significance. Growing evidence indicates that microRNA-486 significantly impacts the development of muscle atrophy. MicroRNA-486 has great potential to become a therapeutic target for improving muscle atrophy through exercise intervention.

Screening of key genes in the pathogenesis of muscle atrophy in CKD-PEW children based on RNA sequencing

BackgroundIn children with CKD, Protein Energy Wasting (PEW) is common, which affects the outcome of children and is an important cause of poor prognosis. We are aiming to explore the pathogenesis of muscle wasting in CKD-PEW children.MethodsBlood samples of 32 children diagnosed with chronic kidney disease (CKD) and protein energy wasting (PEW) in our hospital from January 2016 to June 2021 were collected. RNA sequencing and bioinformatics analysis were performed.ResultsBased on GO (Gene Ontology) functional enrichment analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis and differential gene expression analysis, a total of 25 CKD-PEW related genes were obtained including CRP, IL6, TNF, IL1B, CXCL8, IL12B, IL12A, IL18, IL1A, IL4, IL10, TGFB2, TGFB1, TGFB3, ADIPOQ, NAMPT, RETN, RETNLB, LEP, CD163, ICAM1, VCAM1, SELE, NF-κB1, NF-κB2. The most significantly differentially expressed gene was NF-κB2 (adjusted P = 2.81 × 10–16), and its expression was up-regulated by 3.92 times (corresponding log2FoldChange value was 1.979). Followed by RETN (adjusted P = 1.63 × 10–7), and its expression was up-regulated by 8.306 times (corresponding log2FoldChange value was 2.882). SELE gene were secondly significant (adjusted P = 5.81 × 10–7), and its expression was down-regulated by 22.05 times (corresponding log2FoldChange value was -4.696).ConclusionsA variety of inflammatory factors are involved in the pathogenesis of CKD-PEW in children, and chronic inflammation may lead to the development of muscle atrophy in CKD-PEW. It is suggested for the first time that NF-κB is a key gene in the pathogenesis of muscle wasting in CKD-PEW children, and its increased expression may play an important role in the pathogenesis of muscle wasting in children with CKD-PEW.

A Comparative Study of Deep Learning Approaches for Amyotrophic Lateral Sclerosis Super-Resolution Image Classification

Amyotrophic lateral sclerosis is a fatal degenerative neurological disease known as motor neuron disease. According to research, amyotrophic lateral sclerosis affects nerve cells related to movement in the brain and spinal cord, leading to the death of motor neurons, making the brain unable to control muscle movement, and resulting in a significant loss of motor nerve cells, leading to muscle atrophy. In the early stages of ALS, symptoms are mild, often go unnoticed, and can easily be confused with other diseases. Patients may only feel symptoms such as weakness, convulsions, and fatigue, gradually develop muscle atrophy all over the body, difficulty swallowing, and finally die of respiratory failure. TDP-43 is a DNA/RNA binding protein typically located in the nucleus regulating various steps of RNA metabolism. Meanwhile, TDP-43 is the most prominent pathological protein in the characteristics of ALS patients.[1] TDP-43 is depleted in the nucleus in nearly all ALS cases but accumulates in the cytoplasm.Deep learning is learning the internal laws and representation levels of sample data. The information obtained from these learning processes can significantly help interpret data such as text, images, and sounds. Its goal is to enable machines to analyze and learn like humans and recognize data. Additionally, super-resolution microscopy can be used to observe the conformation of proteins in biological samples, thereby gaining insight into the structure and assembly mechanism of TDP-43 aggregates.This project aims to use super-resolution images for machine learning to build a model for classifying ALS patients from non-ALS patients. At the same time, multiple neural network models are used for training and then compared to select the model with the highest accuracy.

INFLAMMATORY BOWEL DISEASE AND SARCOPENIA: A FOCUS ON MUSCLE STRENGTH - NARRATIVE REVIEW.

•Muscle strength decline is a crucial factor for the course of sarcopenia in inflammatory bowel disease (IBD) patients. •There is a need to discuss the association between IBD and sarcopenia focusing not only on changes of muscle mass, but also on muscle strength. •A narrative review was conducted in order to present the set of factors with impact in both muscle strength and IBD. •Inflammation, reduced nutrient intake and malabsorption, changes in body composition and gut microbiota dysbiosis are most likely the main factors with impact on muscle strength in IBD patients. Inflammation, changes in nutrient absorption and gut dysbiosis are common conditions in patients with inflammatory bowel disease. These factors may lead to variations in macro- and micronutrients and, particularly, to an imbalance of protein metabolism, loss of muscle mass and development of sarcopenia. This narrative review aims to present the set of factors with impact in muscle strength and physical performance that may potentially mediate the relation between inflammatory bowel disease and sarcopenia. Studies that associated changes in muscle strength, sarcopenia and inflammatory bowel disease were selected through a literature search in databases Medline, Pubmed and Scielo using relevant keywords: muscle strength, physical performance, sarcopenia and inflammatory bowel disease. Chronic inflammation is currently reported as a determinant factor in the development of muscle atrophy in inflammatory bowel disease. In addition, strength decline in inflammatory bowel disease patients may be also influenced by changes in body composition and by gut dysbiosis. Measures of muscle strength and physical performance should be considered in the initial identification of sarcopenia, particularly in patients with inflammatory bowel disease, for a timely intervention can be provided. Presence of proinflammatory cytokines, high adiposity, malabsorption and consequent deficits of macro and micronutrients, loss of muscle mass, and gut dysbiosis may be the main factors with impact in muscle strength, that probably mediate the relation between inflammatory bowel disease and sarcopenia.

Poster 363: Post-Operative Protein Supplementation following Orthopaedic Surgery: A Systematic Review

Objectives: Decreased mechanical loading after orthopaedic surgery predisposes patients to develop muscle atrophy. The purpose of the study was to assess whether oral protein supplementation can help decrease postoperative muscle atrophy and/or improve patient outcomes following orthopaedic surgery. Methods: A systematic review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The review was registered with the Prospective Register of Systematic Reviews (PROSPERO). A search of the PROSPERO registration did not identify similar prior systematic reviews or meta-analyses. Databases were searched during April 2021 and included: MEDLINE (Pubmed), Embase, Scopus, and Web of Science. Each search contained a combination of the following terms: “orthopaedic procedures” AND “protein” OR “amino acid” AND “dietary supplements” OR “supplementation” OR “supplement.” Orthopaedic procedures were listed individually using the PubMed index of orthopaedic procedures, as well as using the mesh function to extract articles with orthopaedic procedures listed as keywords. Eligibility Criteria The principal inclusion criteria consisted of randomized controlled trials evaluating protein or amino acid regimens as a measure to counteract muscle atrophy following orthopaedic surgery. Articles that evaluated other forms of dietary supplementation or non-orthopaedic procedures were excluded. Control groups included either placebo or a natural history control (i.e. routine post-operative protocol). The scope of surgery was intentionally left broad, to allow for a comparison of protein supplementation effectiveness across different surgical interventions. Each study’s reference list was manually reviewed for additional articles to prevent unintentional exclusion of studies. Two reviewers independently assessed all articles identified by the search strategy and applied the eligibility criteria. Data Extraction The content extracted from each article included: (1) demographic data, (2) protein supplement regimen used, (3) outcomes, (4) complications, and (5) length of follow up. Primary outcomes included functional or physiologic measures of muscle atrophy or strength. Secondary outcomes included patient satisfaction and time to return to sport or work. Data Analysis Quality assessment of studies was performed using Modified Coleman Methodology Scoring (MCMS). Heterogeneity of study design was noted including differences in protocols, measurement techniques, and outcomes measured, which prevented an adequate statistical comparison for meta-analysis. Results: Fourteen studies including 611 patients (224 male, 387 female) were analyzed (Figure 1). Four surgical cohorts were identified: Anterior cruciate ligament reconstruction (ACLR), total hip arthroplasty (THA), hip fractures (THA, revision THA, hip resurfacing), and total knee arthroplasty (TKA). The ACLR, THA, and hip fracture cohorts were each composed of 3 studies, while there were 5 studies in the TKA cohort. Average length of follow-up was 9 weeks for ACLR, 7 weeks for THA, 10 weeks for hip fracture, and 7 weeks for TKA. Protein supplementation included various combinations of essential amino acids in tablet form or whey protein powder. Placebo supplements were most commonly an isocaloric carbohydrate tablet or powder. Protein supplementation was reported to have beneficial effects across all types of identified surgeries. The primary benefit was decreased muscle atrophy measured by muscle cross sectional area. The most significant difference in muscle atrophy was observed in the final week of follow-up for the majority of studies (average follow up was 8 weeks). Multiple studies also demonstrated improved functional measures, including increased muscle function measured by isokinetic muscle strength. Of note, most participants were involved in some form of formal physical therapy for varying durations after surgery, but this was not standardized across all studies. There were no significant increases in side effects reported comparing protein supplementation cohorts to controls. Of the included investigations, only 2 studies (both for hip fracture) had participants follow a standardized diet. Average MCMS scores for each surgical cohort were as follows: ACLR 55 (fair), TKA 55 (fair), THA 46 (poor), hip fracture 44 (poor). Conclusions: In conclusion, protein supplementation appears to have beneficial effects on mitigating muscle atrophy in the postoperative period following ACLR, THA, TKA, and surgical treatment of hip fracture. This response often correlates with improved functional measures and quicker achievement of rehabilitation benchmarks. Further research is needed to establish standardized supplementation regimens and guidelines for improving clinical outcomes in the postoperative period.

The consequences of physical activity deficit in the applicants of the higher education

Excessive academic workload, nervous overstrain, and physical inactivity are risk factors that cause neurovegetative changes in the body of the applicants of the higher education, which leads to the gradual development of functional disorders and a sharp decline in both mental and physical performance.
 Physical activity helps to improve the physical, mental and functional state, adaptation to environmental conditions, and improve the quality of life in the applicants of the higher education
 Physical activity relieves psycho-emotional fatigue and helps to restore somatic strength, as well as improves physical and mental qualities that allow you to freely control your actions and regulate the process of mental activity. The inclusion of physical exercises in the daily routine of higher education students significantly improves mental performance. Today, this contingent is experiencing a significant decrease in physical activity.
 The purpose of the study: to investigate the consequences of physical activity deficit in higher education students. Results of the study. The consequences of a sedentary lifestyle among students are considered. Conclusions. Physical activity deficit has a negative impact on health, physical development, physical fitness and performance; it is the main cause of non-communicable diseases; causes an increased risk of developing cardiovascular diseases, hypertension, diabetes, breast cancer, depression, frequent respiratory diseases, decreased immune system activity, chronic diseases, metabolic disorders, internal organ function, and posture, deterioration of the mental state, weakening of physical functions, functional disorders, development of muscle atrophy, deterioration of the body's functional reserves, reduced mental performance, and the body's defence mechanisms against adverse environmental influences in the applicants of the institutions of the higher education.

Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation

Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.

Excessive Ethanol Intake in Mice Does Not Impair Recovery of Torque after Repeated Bouts of Eccentric Contractions.

Alcoholics develop muscle atrophy and weakness from excessive ethanol (EtOH) intake. To date, most research has examined outcomes of alcohol-induced atrophy and weakness under basal or unstressed conditions despite physical stress being a normal occurrence in a physiological setting. Therefore, this study set out to determine if recovery of torque is impaired after repetitive bouts of physical stress in skeletal muscle during excessive short-term (experiment 1) and long-term (experiment 2) EtOH consumption. Twenty male and female mice were assigned to receive either 20% EtOH in their drinking water or 100% water. Short- and long-term consumption was predetermined to be EtOH intake starting at 4 and 26 wk, respectively. Anterior crural muscles performed repeated bouts of physical stress using in vivo eccentric contractions, with tetanic isometric torque being measured immediately pre- and postinjury. A total of 10 bouts were completed with 14 d between each bout within bouts 1-5 (experiment 1) and bouts 6-10 (experiment 2), and 12 wk between bouts 5 and 6. Mice consuming EtOH had blood alcohol concentrations up to 270 mg·dL -1 . In experiment 1, five bouts of eccentric contractions did not reduce recovery of torque, regardless of sex or EtOH treatment ( P ≥ 0.173). Similarly, in experiment 2, preinjury torques did not differ from day 14 values regardless of sex or treatment ( P ≥ 0.322). However, there was a group effect in female mice for bouts 6 and 10 during experiment 2, with female EtOH mice being weaker than controls ( P ≤ 0.002). Excessive short- or long-term EtOH misuse in a mouse model did not affect the muscle's ability to regain strength after repeated bouts of eccentric contractions, suggesting that EtOH may not be as detrimental to recovery as once predicted.

Apol9a regulates myogenic differentiation via the ERK1/2 pathway in C2C12 cells.

Background: The rising prevalence of obesity and its complications is a big challenge for the global public health. Obesity is accompanied by biological dysfunction of skeletal muscle and the development of muscle atrophy. The deep knowledge of key molecular mechanisms underlying myogenic differentiation is crucial for discovering novel targets for the treatment of obesity and obesity-related muscle atrophy. However, no effective target is currently known for obesity-induced skeletal muscle atrophy. Methods: Transcriptomic analyses were performed to identify genes associated with the regulation of myogenic differentiation and their potential mechanisms of action. C2C12 cells were used to assess the myogenic effect of Apol9a through immunocytochemistry, western blotting, quantitative polymerase chain reaction, RNA interference or overexpression, and lipidomics. Results: RNA-seq of differentiated and undifferentiated C2C12 cells revealed that Apol9a expression significantly increased following myogenic differentiation and decreased during obesity-induced muscle atrophy. Apol9a silencing in these C2C12 cells suppressed the expression of myogenesis-related genes and reduced the accumulation of intracellular triglycerides. Furthermore, RNA-seq and western blot results suggest that Apol9a regulates myogenic differentiation through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This assumption was subsequently confirmed by intervention with PD98059. Conclusion: In this study, we found that Apol9a regulates myogenic differentiation via the ERK1/2 pathway. These results broaden the putative function of Apol9a during myogenic differentiation and provide a promising therapeutic target for intervention in obesity and obesity-induced muscle atrophy.

Neuromuscular electrical stimulation in the intensive care unit prevents muscle atrophy in critically ill older patients: A retrospective cohort study.

Critically ill patients in the intensive care unit (ICU) develop muscle atrophy and decreased physical function. Though neuromuscular electrical stimulation (NMES) therapy has been shown to be effective in preventing this, but its effect on older patients is unknown.To examine the course of critically ill older patients treated with NMES in the ICU and to define the impact of its use.A retrospective cohort study was conducted using older ICU patients (≥65 years) categorized into a control group (n = 20) and an NMES group (n = 22). For subgroup analysis, each group was further classified into pre-old age (65–74 years) and old age (≥75 years).The control group showed significant decrease in muscle thickness during ICU and hospital stay. The NMES group showed lower reduction in muscle thickness and showed decrease in muscle echo intensity during hospital stay, compared to the control group. NMES inhibited decrease in muscle thickness in the pre-old age group versus the old age group. The decreasing effect of NMES on echo intensity during hospital stay manifested only in the pre-old age group. We did not find much difference in physical functioning between the NMES and control groups.Lower limb muscle atrophy reduces in critically ill older patients (≥65 years) with NMES and is pronounced in patients aged < 75 years. The impact of NMES on the physical functioning of older patients in ICU needs to be further investigated.

IL-17A contributes to skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.

Eicosapentaenoic acid suppresses cisplatin-induced muscle atrophy by attenuating the up-regulated gene expression of ubiquitin

Previously it was shown that cisplatin causes muscle atrophy. Under this condition, cisplatin increased the expression of atorogenes, such as muscle ring finger 1 and atrogin-1 (also known as muscle atrophy F-box protein), in mouse skeletal muscle. It was reported recently that ubiquitin (Ub) and ubiquitinated protein levels in skeletal muscle were also up-regulated in cisplatin-induced muscle atrophy, and cisplatin-induced ubiquitinated proteins were degraded by the 26S proteasome pathway. Eicosapentaenoic acid (EPA) is effective against skeletal muscle atrophy in mice. However, it is unclear how EPA suppresses the Ub–proteasome pathway. In this study, the effect of EPA on cisplatin-induced muscle atrophy in mice was examined. Mice were intraperitoneally injected with cisplatin or vehicle control once daily for 4 d. EPA or its vehicle was orally administered 30 min before cisplatin administration. Cisplatin systemic administration induced decrease in muscle mass, myofiber diameter, and increase in Ub genes and ubiquitinated proteins in mouse skeletal muscle were recovered by co-treatment with EPA. However, weight loss and up-regulated atrogenes induced by cisplatin were not changed by co-treatment with EPA in skeletal muscle. In this study, EPA attenuated cisplatin-induced muscle atrophy via down-regulation of up-regulated Ub gene expression. Although further clinical studies are needed, EPA administration can be effective in the development of muscle atrophy in cisplatin-treated patients.

Is paravertebral muscles edema a consequence of neurogenic changes in MuSK-positive myasthenia gravis?

Anti-MuSK myasthenia gravis (Anti-MuSK MG) is a chronic autoimmune disease caused by complement-independent dysfunction of the agrin-MuSK-Lrp4 complex, accompanied by the development of the pathological muscle fatigue and sometimes muscle atrophy. Fatty replacement of the tongue, mimic, masticatory and paravertebral muscles, revealed by muscle MRI and proton magnetic resonance spectroscopy (MRS), is considered to be a consequence of the myogenic process in anti-MuSK antibody MG in the patients with a plenty long course of the disease. However, in most experimental studies on animal models with anti-MuSK MG, complex presynaptic and postsynaptic changes are revealed, accompanied by the functional denervation of masticatory and paravertebral muscles predominantly. This study presents the MRI, nerve conduction studies (NCS), repetitive nerve stimulation (RNS) and electromyography (EMG) of neurogenic lesions of the axial muscles (m. Multifidus Th12, L3-L5; m. Erector spinae L4-L5) in two patients K. (51 years old), and P. (44 years old), both of whom were having weakness of the paravertebral muscles for 2-4 months due to anti-MuSK MG. The clinical manifestations, as well as the edematous changes in the paravertebral muscles, regressed after therapy. Thus, these clinical examples may confirm the presence of the neurogenic changes at an early stage of anti-MuSK myasthenia gravis and indicate importance of immediate initiation of therapy to avoid the development of muscle atrophy and fatty infiltration.

Generation of DMBi002-A human induced pluripotent stem cell line from patient with Spinal muscular atrophy type 3

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease caused by mutations inSMN1 gene encoding survival motor neuron (SMN) protein. Lack of this protein leads to progressive loss of motor neurons and therefore to gradual loss of signal transmission between motor neurons and skeletal muscle cells. As a consequence, patients develop muscle atrophy and lose the ability to move independently, what is also related to problems with breathing and swallowing. Here, we describe the generation of human induced pluripotent stem cells (hiPSC) from peripheral blood mononuclear cells (PBMC) of adult SMA type 3 patient with a use of Sendai virus vectors.

Hepatic Steatosis Contributes to the Development of Muscle Atrophy via Inter-Organ Crosstalk.

Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200-µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomics analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like growth factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.

Dexamethasone Inhibits the Pro-Angiogenic Potential of Primary Human Myoblasts.

Tissue regeneration depends on the complex processes of angiogenesis, inflammation and wound healing. Regarding muscle tissue, glucocorticoids (GCs) inhibit pro-inflammatory signalling and angiogenesis and lead to muscle atrophy. Our hypothesis is that the synthetic GC dexamethasone (dex) impairs angiogenesis leading to muscle atrophy or inhibited muscle regeneration. Therefore, this study aims to elucidate the effect of dexamethasone on HUVECs under different conditions in mono- and co-culture with myoblasts to evaluate growth behavior and dex impact with regard to muscle atrophy and muscle regeneration. Viability assays, qPCR, immunofluorescence as well as ELISAs were performed on HUVECs, and human primary myoblasts seeded under different culture conditions. Our results show that dex had a higher impact on the tube formation when HUVECs were maintained with VEGF. Gene expression was not influenced by dex and was independent of cells growing in a 2D or 3D matrix. In co-culture CD31 expression was suppressed after incubation with dex and gene expression analysis revealed that dex enhanced expression of myogenic transcription factors, but repressed angiogenic factors. Moreover, dex inhibited the VEGF mediated pro angiogenic effect of myoblasts and inhibited expression of angiogenic inducers in the co-culture model. This is the first study describing a co-culture of human primary myoblast and HUVECs maintained under different conditions. Our results indicate that dex affects angiogenesis via inhibition of VEGF release at least in myoblasts, which could be responsible not only for the development of muscle atrophy after dex administration, but also for inhibition of muscle regeneration after vascular damage.

Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy.

Imbalance of protein homeostasis, with excessive protein degradation compared with protein synthesis, leads to the development of muscle atrophy resulting in a decrease in muscle mass and consequent muscle weakness and disability. Potential triggers of muscle atrophy include inflammation, malnutrition, aging, cancer, and an unhealthy lifestyle such as sedentariness and high fat diet. Nutraceuticals with preventive and therapeutic effects against muscle atrophy have recently received increasing attention since they are potentially more suitable for long-term use. The implementation of nutraceutical intervention might aid in the development and design of precision medicine strategies to reduce the burden of muscle atrophy. In this review, we will summarize the current knowledge on the importance of nutraceuticals in the prevention of skeletal muscle mass loss and recovery of muscle function. We also highlight the cellular and molecular mechanisms of these nutraceuticals and their possible pharmacological use, which is of great importance for the prevention and treatment of muscle atrophy.

Sarcopenia in patients with chronic kidney disease: prevalence, pathogenesis and clinical significance

Chronic kidney disease (CKD) is a chronic catabolic condition accompanied by sarcopenia, manifested by decreased muscle mass, strength, and endurance. As defined by the European Working Group on Sarcopenia in the Elderly (EWGSOP), sar-copenia is a progressive and generalized skeletal muscle disorder that is associated with an increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality. Its prevalence in patients with CKD, according to various sources, varies from 3.9 to 65.5 %, depending on gender, age, and stage of the disease. It develops as a result of an imbalance between protein degradation and synthesis. The development of muscle atrophy is associated with oxidative stress, inflammation, and leads to the progression of atherosclerosis. This scientific review contains current information on the problem of sar-copenia in patients with CKD, its prevalence, the molecular basis of pathogenesis, as well as its contribution to cardiovascular risk and mortality from cardiovascular diseases in the discussed group.

Master Regulators of Muscle Atrophy: Role of Costamere Components.

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal “signaling hub” integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy.