MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

OAS1 suppresses African swine fever virus replication by recruiting TRIM21 to degrade viral major capsid protein.

IMPORTANCE: African swine fever virus (ASFV) completes the replication process by resisting host antiviral response via inhibiting interferon (IFN) secretion and interferon-stimulated genes (ISGs) function. 2', 5'-Oligoadenylate synthetase gene 1 (OAS1) has been reported to inhibit the replication of various RNA and some DNA viruses. However, the regulatory mechanisms involved in the ASFV-induced IFN-related pathway still need to be fully elucidated. Here, we found that OAS1, as a critical host factor, inhibits ASFV replication in an RNaseL-dependent manner. Furthermore, overexpression of OAS1 can promote the activation of the JAK-STAT pathway promoting innate immune responses. In addition, OAS1 plays a new function, which could interact with ASFV P72 protein to suppress ASFV infection. Mechanistically, OAS1 enhances the proteasomal degradation of P72 by promoting TRIM21-mediated ubiquitination. Meanwhile, P72 inhibits the production of avSG and affects the interaction between OAS1 and DDX6. Our findings demonstrated OAS1 as an important target against ASFV replication and revealed the mechanisms and intrinsic regulatory relationships during ASFV infection.

Celecoxib attenuates hindlimb unloading-induced muscle atrophy via suppressing inflammation, oxidative stress and ER stress by inhibiting STAT3.

Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy.

The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration.

BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Mitochondrial dysfunction: roles in skeletal muscle atrophy.

Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-ß-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.

Altered m6A RNA methylation governs denervation-induced muscle atrophy by regulating ubiquitin proteasome pathway.

BACKGROUND: Denervation-induced muscle atrophy is complex disease involving multiple biological processes with unknown mechanisms. N6-methyladenosine (m6A) participates in skeletal muscle physiology by regulating multiple levels of RNA metabolism, but its impact on denervation-induced muscle atrophy is still unclear. Here, we aimed to explore the changes, functions, and molecular mechanisms of m6A RNA methylation during denervation-induced muscle atrophy. METHODS: During denervation-induced muscle atrophy, the m6A immunoprecipitation sequencing (MeRIP-seq) as well as enzyme-linked immunosorbent assay analysis were used to detect the changes of m6A modified RNAs and the involved biological processes. 3-deazidenosine (Daa) and R-2-hydroxyglutarate (R-2HG) were used to verify the roles of m6A RNA methylation. Through bioinformatics analysis combined with experimental verification, the regulatory roles and mechanisms of m6A RNA methylation had been explored. RESULTS: There were many m6A modified RNAs with differences during denervation-induced muscle atrophy, and overall, they were mainly downregulated. After 72 h of denervation, the biological processes involved in the altered mRNA with m6A modification were mainly related to zinc ion binding, ubiquitin protein ligase activity, ATP binding and sequence-specific DNA binding and transcription coactivator activity. Daa reduced overall m6A levels in healthy skeletal muscles, which reduced skeletal muscle mass. On the contrary, the increase in m6A levels mediated by R-2HG alleviated denervation induced muscle atrophy. The m6A RNA methylation regulated skeletal muscle mass through ubiquitin-proteasome pathway. CONCLUSION: This study indicated that decrease in m6A RNA methylation was a new symptom of denervation-induced muscle atrophy, and confirmed that targeting m6A alleviated denervation-induced muscle atrophy.

Alternative splicing transitions associate with emerging atrophy phenotype during denervation-induced skeletal muscle atrophy.

Alternative splicing (AS) presents a key posttranscriptional regulatory mechanism associated with numerous physiological processes. However, little is known about its role in skeletal muscle atrophy. In this study, we used a rat model of denervated skeletal muscle atrophy and performed RNA-sequencing to analyze transcriptome profiling of tibialis anterior muscle at multiple time points following denervation. We found that AS is a novel mechanism involving muscle atrophy, which is independent changes at the transcript level. Bioinformatics analysis further revealed that AS transitions are associated with the appearance of the atrophic phenotype. Moreover, we found that the inclusion of multiple highly conserved exons of Obscn markedly increased at 3 days after denervation. In addition, we confirmed that this newly transcript inhibited C2C12 cell proliferation and exacerbated myotube atrophy. Finally, our study revealed that a large number of RNA-binding proteins were upregulated when the atrophy phenotype appeared. Our data emphasize the importance of AS in this process.

LncRNA H19 induces immune dysregulation of BMMSCs, at least partly, by inhibiting IL-2 production.

BACKGROUND: Systemic lupus erythematosus (SLE) is a representative systemic autoimmune disease. LncRNA H19 has been identified to participate in various biological processes in human diseases. However, the role of H19 in SLE remains unclear. METHODS: In this study, we first examined H19 expression in SLE patients by RT-qPCR and found that H19 expression was significantly upregulated in the serum and bone marrow-derived mesenchymal stem cells (BMMSCs) of SLE patients and positively associated with SLE disease activity index. We then performed gain-of-function and loss-of-function using mimic-H19 (H19-OE) and inhibitor-H19 (H19-KD) to examine the effects of H19 on BMMSC differentiation, proliferation, migration, and apoptosis using flow cytometry, DAPI staining, and migration and apoptosis assays. RESULTS: The results showed that H19 inhibited proliferation and migration but promoted apoptosis of BMMSCs, interfered with BMMSCs-mediated Treg cell proliferation and differentiation, and regulated BMMSCs-mediated Tfh/Treg cell balance. Dual-luciferase reporter assay confirmed the in silico prediction of interaction between H19 and IL-2. Furthermore, RT-qPCR showed that H19 directly inhibited IL-2 transcription in BMMSCs. ELISA showed that both active and total IL-2 protein levels were significantly lower in SLE BMMSCs. More importantly, we found that IL-2 significantly enhanced H19-OE-induced Treg cell differentiation and migration of BMMSCs, and these effects were reversed by anti-IL-2 antibody. CONCLUSION: Overall, our study indicates that LncRNA H19 induces immune dysregulation of BMMSCs, at least partly, by inhibiting IL-2 production and might be a novel therapeutic target for SLE.

TRAF6 inhibition rescues dexamethasone-induced muscle atrophy.

Tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, is involved in activation of various signaling cascades. Recent studies identify TRAF6 as one of the novel regulators of skeletal muscle atrophy. The role of TRAF6 in glucocorticoid-induced muscle atrophy, however, remains to be elucidated. In this study, we show that TRAF6 and its downstream signaling molecules, muscle atrophy F-box (MAFBx) and muscle ring finger 1 (MuRF1), were all upregulated in dexamethasone-induced atrophy of mouse C2C12 myotubes or mouse tibialis anterior (TA) muscle. To further investigate the role of TRAF6 in dexamethasone-induced muscle atrophy, TRAF6-siRNA was used to transfect cultured C2C12 myotubes or was injected into the TA muscle of mice respectively, and we note that TRAF6 knockdown attenuated dexamethasone-induced muscle atrophy in vitro and in vivo, and concomitantly decreased the expression of MuRF1 and MAFBx. Our findings suggest that a decreased expression of TRAF6 could rescue dexamethasone-induced skeletal muscle atrophy through, at least in part, regulation of the expression of MAFBx and MuRF1.

Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms.

Skeletal muscle can undergo detrimental changes in various diseases, leading to muscle dysfunction and atrophy, thus severely affecting people's lives. Along with exercise, there is a growing interest in the potential of nutritional support against muscle atrophy. This review provides a brief overview of the molecular mechanisms driving skeletal muscle atrophy and summarizes recent advances in nutritional interventions for preventing and treating muscle atrophy. The nutritional supplements include amino acids and their derivatives (such as leucine, ß-hydroxy, ß-methylbutyrate, and creatine), various antioxidant supplements (like Coenzyme Q10 and mitoquinone, resveratrol, curcumin, quercetin, Omega 3 fatty acids), minerals (such as magnesium and selenium), and vitamins (such as vitamin B, vitamin C, vitamin D, and vitamin E), as well as probiotics and prebiotics (like Lactobacillus, Bifidobacterium, and 1-kestose). Furthermore, the study discusses the impact of a combined approach involving nutritional support and physical therapy to prevent muscle atrophy, suggests appropriate multi-nutritional and multi-modal interventions based on individual conditions to optimize treatment outcomes, and enhances the recovery of muscle function for patients. By understanding the molecular mechanisms behind skeletal muscle atrophy and implementing appropriate interventions, it is possible to enhance the recovery of muscle function and improve patients' quality of life.

The Schwann cell-specific G-protein Gαo (Gnao1) is a cell-intrinsic controller contributing to the regulation of myelination in peripheral nerve system.

Myelin sheath abnormality is the cause of various neurodegenerative diseases (NDDs). G-proteins and their coupled receptors (GPCRs) play the important roles in myelination. Gnao1, encoding the major Gα protein (Gαo) in mammalian nerve system, is required for normal motor function. Here, we show that Gnao1 restricted to Schwann cell (SCs) lineage, but not neurons, negatively regulate SC differentiation, myelination, as well as re-myelination in peripheral nervous system (PNS). Mice lacking Gnao1 expression in SCs exhibit faster re-myelination and motor function recovery after nerve injury. Conversely, mice with Gnao1 overexpression in SCs display the insufficient myelinating capacity and delayed re-myelination. In vitro, Gnao1 deletion in SCs promotes SC differentiation. We found that Gnao1 knockdown in SCs resulting in the elevation of cAMP content and the activation of PI3K/AKT pathway, both associated with SC differentiation. The analysis of RNA sequencing data further evidenced that Gnao1 deletion cause the increased expression of myelin-related molecules and activation of regulatory pathways. Taken together, our data indicate that Gnao1 negatively regulated SC differentiation by reducing cAMP level and inhibiting PI3K-AKT cascade activation, identifying a novel drug target for the treatment of demyelinating diseases.

Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems.

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear. Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy. Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles. Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

Establishment of an ELISA Based on a Recombinant Antigenic Protein Containing Multiple Prominent Epitopes for Detection of African Swine Fever Virus Antibodies.

African swine fever virus (ASFV) poses a significant threat to the global pig industry, necessitating accurate and efficient diagnostic methods for its infection. Previous studies have often focused on a limited number of epitopes from a few proteins for detecting antibodies against ASFV. Therefore, the current study aimed to use multiple B-cell epitopes in developing an indirect Enzyme-Linked Immunosorbent Assay (ELISA) for enhanced detection of ASFV antibodies. For the expression of recombinant protein, k3 derived from 27 multiple peptides of 11 ASFV proteins, such as p72, pA104R, pB602L, p12, p14.5, p49, pE248R, p30, p54, pp62, and pp220, was used. To confirm the expression of the recombinant protein, we used the Western blotting analysis. The purified recombinant K3 protein served as the antigen in our study, and we employed the indirect ELISA technique to detect anti-ASFV antibodies. The present finding showed that there was no cross-reactivity with antibodies targeting Foot-and-mouth disease virus (FMDV), Porcine circovirus type 2 (PCV2), Pseudorabies virus (PRV), Porcine reproductive and respiratory syndrome virus (PRRSV), and Classical swine fever virus (CSFV). Moreover, the current finding was sensitive enough to find anti-ASFV in serum samples that had been diluted up to 32 times. The test (k3-iELISA) showed diagnostic specificity and sensitivity of 98.41% and 97.40%, respectively. Moreover, during the present investigation, we compared the Ingenasa kit and the k3-iELISA to test clinical pig serum, and the results revealed that there was 99.00% agreement between the two tests, showing good detection capability of the k3-iELISA method. Hence, the current finding showed that the ELISA kit we developed can be used for the rapid detection of ASFV antibodies and used as an alternative during serological investigation of ASF in endemic areas.

MircoRNA-25-3p in skin precursor cell-induced Schwann cell-derived extracellular vesicles promotes axon regeneration by targeting Tgif1.

Nerve injury often leads to severe dysfunction because of the lack of axon regeneration in adult mammal. Intriguingly a series of extracellular vesicles (EVs) have the obvious ability to accelerate the nerve repair. However, the detailed molecular mechanisms to describe that EVs switch neuron from a transmitter to a regenerative state have not been elucidated. This study elucidated the microRNA (miRNA) expression profiles of two types of EVs that promote nerve regeneration. The functions of these miRNAs were screened in vitro. Among the 12 overlapping miRNAs, miR-25-3p was selected for further analysis as it markedly promoted axon regeneration both in vivo and in vitro. Furthermore, knockdown experiments confirmed that PTEN and Klf4, which are the major inhibitors of axon regeneration, were the direct targets of miR-25-3p in dorsal root ganglion (DRG) neurons. The utilization of luciferase reporter assays and functional tests provided evidence that miR-25-3p enhances axon regeneration by targeting Tgif1. Additionally, miR-25-3p upregulated the phosphorylation of Erk. Furthermore, Rapamycin modulated the expression of miR-25-3p in DRG neurons. Finally, the pro-axon regeneration effects of EVs were confirmed by overexpressing miR-25-3p and Tgif1 knockdown in the optic nerve crush model. Thus, the enrichment of miR-25-3p in EVs suggests that it regulates axon regeneration, proving a potential cell-free treatment strategy for nerve injury.

A narrative review on traditional Chinese medicine prescriptions and bioactive components in epilepsy treatment.

Background and Objective: In traditional Chinese medicine (TCM), natural drugs and their bioactive components have been widely used to treat epilepsy. Epilepsy is a chronic disease caused by abnormal discharge of brain neurons that leads to brain dysfunction and cognitive impairment. Several factors are involved in the mechanisms of epilepsy, and the current treatments do not seem promising. The potential efficacy of natural drugs with lower toxicity and less side effects have attracted increasing attention. Methods: We used the terms, "TCM", "traditional Chinese medicine", "herbal", "epilepsy", "seizure", and the name of each prescription and bioactive components in the review to collect papers about application of TCM in epilepsy treatment from PubMed online database and Chinese database including Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Key Content and Findings: We summarized some common TCM prescriptions and related active components used for the treatment of epilepsy. Six prescriptions (Chaihu Shugan decoction, Tianma Gouteng decoction, Kangxian capsules, Taohong Siwu decoction, Liujunzi decoction, Compound Danshen dropping pills) and nine main bioactive compounds (Saikosaponin A, Rhynchophylline, Tetramethylpyrazine, Gastrodin, Baicalin and baicalein, α-Asarone, Ginsenoside, Tanshinone, Paeoniflorin) were reviewed to provide a scientific basis for the development of potential antiepileptic drugs (AEDs). Conclusions: The pharmacological effects and molecular mechanisms of TCM in the treatment of epilepsy are complex, targeting several pathological aspects of epilepsy. However, the limitations of TCM, such as the lack of standardized treatments, have prevented its clinical application in epilepsy treatment. Thus, additional clinical trials are required to further evaluate the effectiveness and safety of TCM prescriptions and their bioactive components in the future.

SnRNA-seq reveals the heterogeneity of spinal ventral horn and mechanism of motor neuron axon regeneration.

Spinal motor neurons, the distinctive neurons of the central nervous system, extend into the peripheral nervous system and have outstanding ability of axon regeneration after injury. Here, we explored the heterogeneity of spinal ventral horn cells after rat sciatic nerve crush via single-nuclei RNA sequencing. Interestingly, regeneration mainly occurred in a Sncg+ and Anxa2+ motor neuron subtype (MN2) surrounded by a newly emerged microglia subtype (Mg6) after injury. Subsequently, microglia depletion slowed down the regeneration of sciatic nerve. OPCs were also involved into the regeneration process. Knockdown of Cacna2d2 in vitro and systemic blocking of Cacna2d2 in vivo improved the axon growth ability, hinting us the importance of Ca2+. Ultimately, we proposed three possible phases of motor neuron axon regeneration: preparation stage, early regeneration stage, and regeneration stage. Taken together, our study provided a resource for deciphering the underlying mechanism of motor neuron axon regeneration in a single cell dimension.

Chronic kidney disease-induced muscle atrophy: Molecular mechanisms and promising therapies.

Chronic kidney disease (CKD) is a high-risk chronic catabolic disease due to its high morbidity and mortality. CKD is accompanied by many complications, leading to a poor quality of life, and serious complications may even threaten the life of CKD patients. Muscle atrophy is a common complication of CKD. Muscle atrophy and sarcopenia in CKD patients have complex pathways that are related to multiple mechanisms and related factors. This review not only discusses the mechanisms by which inflammation, oxidative stress, mitochondrial dysfunction promote CKD-induced muscle atrophy but also explores other CKD-related complications, such as metabolic acidosis, vitamin D deficiency, anorexia, and excess angiotensin II, as well as other related factors that play a role in CKD muscle atrophy, such as insulin resistance, hormones, hemodialysis, uremic toxins, intestinal flora imbalance, and miRNA. We highlight potential treatments and drugs that can effectively treat CKD-induced muscle atrophy in terms of complication treatment, nutritional supplementation, physical exercise, and drug intervention, thereby helping to improve the prognosis and quality of life of CKD patients.

Oxidative stress: Roles in skeletal muscle atrophy.

Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.

Myasthenia gravis: Molecular mechanisms and promising therapeutic strategies.

Myasthenia gravis (MG) is a type of autoimmune disease caused by the blockage of neuromuscular junction transmission owing to the attack of autoantibodies on transmission-related proteins. Related antibodies, such as anti-AChR, anti-MuSK and anti-LRP4 antibodies, can be detected in most patients with MG. Although traditional therapies can control most symptoms, several challenges remain to be addressed, necessitating the development of more effective and safe treatment strategies for MG. With the in-depth exploration on the mechanism and immune targets of MG, effective therapies, especially therapies using biologicals, have been reported recently. Given the important roles of immune cells, cytokines and intercellular interactions in the pathological process of MG, B-cell targeted therapy, T-cell targeted therapy, proteasome inhibitors targeting plasma cell, complement inhibitors, FcRn inhibitors have been developed for the treatment of MG. Although these novel therapies exert good therapeutic effects, they may weaken the immunity and increase the risk of infection in MG patients. This review elaborates on the pathogenesis of MG and discusses the advantages and disadvantages of the strategies of traditional treatment and biologicals. In addition, this review emphasises that combined therapy may have better therapeutic effects and reducing the risk of side effects of treatments, which has great prospects for the treatment of MG. With the deepening of research on immunotherapy targets in MG, novel opportunities and challenges in the treatment of MG will be introduced.

Duchenne muscular dystrophy: pathogenesis and promising therapies.

Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disease, characterized by progressive deterioration of skeletal muscle that causes rapid loss of mobility. The failure in respiratory and cardiac muscles is the underlying cause of premature death in most patients with DMD. Mutations in the gene encoding dystrophin result in dystrophin deficiency, which is the underlying pathogenesis of DMD. Dystrophin-deficient myocytes are dysfunctional and vulnerable to injury, triggering a series of subsequent pathological changes. In this review, we detail the molecular mechanism of DMD, dystrophin deficiency-induced muscle cell damage (oxidative stress injury, dysregulated calcium homeostasis, and sarcolemma instability) and other cell damage and dysfunction (neuromuscular junction impairment and abnormal differentiation of muscle satellite). We also describe aberrant function of other cells and impaired muscle regeneration due to deterioration of the muscle microenvironment, and dystrophin deficiency-induced multiple organ dysfunction, while summarizing the recent advances in the treatment of DMD.