Skeletal Muscle Inflammation Research Articles

Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective.

Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myofiber pathways. These pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. This review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.

Stachydrine alleviates lipid-induced skeletal muscle insulin resistance via AMPK/HO-1-mediated suppression of inflammation and endoplasmic reticulum stress.

Insulin resistance develops due to skeletal muscle inflammation and endoplasmic reticulum (ER) stress. Stachydrine (STA), extracted from Leonurus heterophyllus, has been shown to suppress proliferation and induce apoptosis in breast cancer cells and exert anti-inflammatory properties in the brain, heart, and liver. However, the roles of STA in insulin signaling in skeletal muscle remain unclear. Herein, we examined the impacts of STA on insulin signaling in skeletal muscle under hyperlipidemic conditions and its related molecular mechanisms. Various protein expression levels were determined by Western blotting. Levels of mouse serum cytokines were measured by ELISA. We found that STA-ameliorated inflammation and ER stress, leading to attenuation of insulin resistance in palmitate-treated C2C12 myocytes. STA dose-dependently enhanced AMPK phosphorylation and HO-1 expression. Administration of STA attenuated not only insulin resistance but also inflammation and ER stress in the skeletal muscle of high-fat diet (HFD)-fed mice. Additionally, STA-ameliorated glucose tolerance and insulin sensitivity, as well as serum TNFα and MCP-1, in mice fed a HFD. Small interfering (si) RNA-associated suppression of AMPK or HO-1 expression abolished the effects of STA in C2C12 myocytes. These results suggest that STA activates AMPK/HO-1 signaling, resulting in reduced inflammation and ER stress, thereby improving skeletal muscle insulin resistance. Using STA as a natural ingredient, this research successfully treated insulin resistance and type 2 diabetes.

Trypanosoma cruzi blood trypomastigotes induce intense skeletal and cardiac muscle damage and Th1/ Th2 immune response in the acute phase of mice infected by the oral route

Oral acquisition of Trypanosoma cruzi is a foodborne transmission by juices and fruits contaminated with metacyclic trypomastigotes (MT) or by the ingestion of wild reservoirs infected with blood trypomastigotes (BT). In Mexico, hunting and food consumption of wild animals are current practices, which could represent a risk factor for oral infection in the rural population. In this work, Balb/c mice were inoculated by oral route with BT of a highly virulent T. cruzi Mexican strain (DTU I) to evaluate the establishment of the infection, and the humoral and cellular immune response in the acute phase of the infection. We show that BT induces blood and tissue parasitism producing an inflammatory process in the heart and skeletal muscle and low parasitism and inflammation in the digestive tract of orally infected mice. Besides, in the acute phase, the BT promotes splenomegaly, intense damage in skeletal and cardiac muscles, a humoral response dominated by the IgG isotype, and the expression of pro-inflammatory cytokines.

Effect of Creatine Supplementation on the Muscular Inflammation and Muscle Atrophy in High-Fat High-Fructose Fed Obese Growing Rats

Objective: This study aimed to investigate effects of creatine supplementation on high-fat high-fructose fed obese rats. Twenty-four six-week-old male Sprague-Dawley rats were randomly divided into three groups (n=8 each): control sedentary group (CD), high-fat high-fructose diet group (HD), and creatine-supplemented high-fat high-fructose diet group (CHD). Methodology: The CD group was supplemented with AIN-76G diet, and a high-fat high-fructose diet for HD and CHD groups was substituted with 5% corn oil fat to 35% lard. The CHD group was supplemented with 2% creatine. The total soleus muscle protein was extracted and prepared according to the procedure mentioned by Baghirova et al. for muscle cytokine assay and western blotting. Result: After eight weeks of the experimental period, weights of the soleus muscle in the HD and CHD groups were significantly lower than that in the CD group. In addition, levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α in the HD groups were significantly higher than those in the CD group. In contrast, IL-1β, IL-6 concentrations in the CHD group were significantly lower than those in the HD group and irisin levels of HD and CHD group were significantly lower than those in the CD group. Moreover, levels of muscle protein degradation factors [Muscle RING-finger protein-1 (MuRF1) and atrogin-1] were significantly higher in the HD and CHD groups than those in the CD group. Conclusion: From these results, it was concluded that creatine supplementation attenuates the inflammation of skeletal muscle via pro-inflammatory cytokines; however, it has no significant role in preventing muscular atrophy in high-fat high-fructose fed obese rats.

Influences of Vitamin D and Iron Status on Skeletal Muscle Health: A Narrative Review.

There is conflicting evidence of the roles vitamin D and iron have in isolation and combined in relation to muscle health. The purpose of this narrative review was to examine the current literature on the roles that vitamin D and iron have on skeletal muscle mass, strength, and function and how these nutrients are associated with skeletal muscle health in specific populations. Secondary purposes include exploring if low vitamin D and iron status are interrelated with skeletal muscle health and chronic inflammation and reviewing the influence of animal-source foods rich in these nutrients on health and performance. PubMed, Scopus, SPORT Discus, EMBAE, MEDLINE, and Google Scholar databases were searched to determine eligible studies. There was a positive effect of vitamin D on muscle mass, particularly in older adults. There was a positive effect of iron on aerobic and anaerobic performance. Studies reported mixed results for both vitamin D and iron on muscle strength and function. While vitamin D and iron deficiency commonly occur in combination, few studies examined effects on skeletal muscle health and inflammation. Isolated nutrients such as iron and vitamin D may have positive outcomes; however, nutrients within food sources may be most effective in improving skeletal muscle health.

Eggshell membrane modulates gut microbiota to prevent murine pre-cachexia through suppression of T helper cell differentiation.

BackgroundCachexia is a life‐threatening condition observed in several pathologies, such as cancer or chronic diseases. Interleukin 10 (Il10) gene transfer is known to improve cachexia by downregulating Il6. Here, we used an IL10‐knockout mouse model to simulate cachexia and investigate the effects of eggshell membrane (ESM), a resistant protein, on general pre‐cachexia symptoms, which is particularly important for the development of cachexia therapeutics.MethodsFive‐week‐old male C57BL6/J mice were fed an AIN‐93G powdered diet (WT), and 5‐week‐old male B6.129P2‐Il10 < tm1Cgn>/J (IL10−/−) mice were fed either the AIN‐93G diet (KO) or an 8% ESM‐containing diet (KOE) for 28 weeks. The tissue weight and levels of anaemia‐, blood glucose‐, lipid metabolism‐, and muscular and colonic inflammation‐related biochemical markers were measured. Transcriptomic analysis on liver and colon mucus and proteomic analysis on skeletal muscle were performed. Ingenuity Pathway Analysis was used to identify molecular pathways and networks. Caecal short‐chain fatty acids (SCFAs) were identified using HPLC, and caecal bacteria DNA were subjected to metagenomic analysis. Flow cytometry analysis was performed to measure the CD4+ IL17+ T cells in mesenteric lymph nodes.ResultsThe body weight, weight of gastrocnemius muscle and fat tissues, colon weight/length ratio, plasma HDL and NEFA, muscular PECAM‐1 levels (P < 0.01), plasma glucose and colonic mucosal myeloperoxidase activity (P < 0.05) and T helper (Th) 17 cell abundance (P = 0.071) were improved in KOE mice over KO mice. Proteomic analysis indicated the protective role of ESM in muscle weakness and maintenance of muscle formation (>1.5‐fold). Transcriptomic analysis revealed that ESM supplementation suppressed the LPS/IL1‐mediated inhibition of RXR function pathway in the liver and downregulated the colonic mucosal expression of chemokines and Th cell differentiation‐related markers (P < 0.01) by suppressing the upstream BATF pathway. Analysis of the intestinal microenvironment revealed that ESM supplementation ameliorated the microbial alpha diversity and the abundance of microbiota associated with the degree of inflammation (P < 0.05) and increased the level of total organic acids, particularly of SCFAs such as butyrate (2.3‐fold), which could inhibit Th1 and Th17 production.ConclusionsESM supplementation ameliorated the chief symptoms of cachexia, including anorexia, lean fat tissue mass, skeletal muscle wasting and reduced physical function. ESM also improved colon and skeletal muscle inflammation, lipid metabolism and microbial dysbiosis. These results along with the suppressed differentiation of Th cells could be associated with the beneficial intestinal microenvironment and, subsequently, attenuation of pre‐cachexia. Our findings provide insights into the potential of ESM in complementary interventions for pre‐cachexia prevention.

Diagnostic delay of myositis: protocol for an integrated systematic review

IntroductionIdiopathic inflammatory myopathies (IIM). described as ‘inflammatory myositis’, are a heterogeneous group of rare muscular autoimmune diseases characterised by skeletal muscle inflammation. Its complex characteristics with lack of accurate diagnostic...

The Genetics of Autoimmune Myositis.

The idiopathic inflammatory myopathies (IIM) are rare, heterogeneous systemic autoimmune disorders, characterized by inflammation of skeletal muscle and multi-organ involvement. Studies to identify genetic risk factors and dysregulated gene expression in IIM aim to increase our understanding of disease pathogenesis. Genome-wide association studies have confirmed the HLA region as the most strongly associated region in IIM, with different associations between clinically-defined subgroups. Associated genes are involved in both the innate and adaptive immune response, while identification of variants reported in other autoimmune disorders suggests shared biological pathways. Targeted imputation analysis has identified key associated amino acid residues within HLA molecules that may influence antigen recognition. These amino acids increase risk for specific clinical phenotypes and autoantibody subgroups, and suggest that serology-defined subgroups may be more homogeneous. Recent data support the contribution of rare genetic variation to disease susceptibility in IIM, including mitochondrial DNA variation in sporadic inclusion body myositis and somatic mutations and loss of heterozygosity in cancer-associated myositis. Gene expression studies in skeletal muscle, blood and skin from individuals with IIM has confirmed the role of interferon signalling and other dysregulated pathways, and identified cell-type specific signatures. These dysregulated genes differentiate IIM subgroups and identify potential biomarkers. Here, we review recent genetic studies in IIM, and how these inform our understanding of disease pathogenesis and provide mechanistic insights into biological pathways.

Inflammation and Wasting of Skeletal Muscles in Kras-p53-Mutant Mice with Intraepithelial Neoplasia and Pancreatic Cancer-When Does Cachexia Start?

Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: −20.0%) and soleus (type 2a: −21.0%, type 1: −14.2%) muscle with accentuation in the male soleus (type 2a: −24.8%, type 1: −17.4%) and female gastrocnemius muscle (−29.6%). Significantly higher densities of endomysial CD68+ and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared to WT mice. Surprisingly, CD68+ and COX2+ cell densities were also higher in mice with PanIN 1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+ or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3) expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT. Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local (and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria. Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic) increases in free amino acids and glutathione were already detectable in mice with precancerous PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted for targeted anti-inflammatory prevention.

Sulforaphane Ameliorates Limb Ischemia/Reperfusion-Induced Muscular Injury in Mice by Inhibiting Pyroptosis and Autophagy via the Nrf2-ARE Pathway.

Background Limb ischemia/reperfusion (I/R) injury, as a life-threatening syndrome, is commonly caused by skeletal muscle damage resulting from oxidative stress. Additionally, inflammation-induced pyroptosis and dysregulated autophagy are vital factors contributing to the aggravation of I/R injury. Of note, sulforaphane (SFN) is a natural antioxidant, but whether it worked in limb I/R injury and the possible mechanism behind its protection for skeletal muscle has not been clearly established. Methods Effects of SFN on limb I/R-injured skeletal muscle were assessed by HE staining, followed by assessment of wet weight/dry weight (W/D) ratio of muscle tissues. Next, ELISA and biochemical tests were used to measure the inflammatory cytokine production and oxidative stress. Immunofluorescent analysis and Western blot were adopted to examine the level of pyroptosis- and autophagy-related proteins in vivo. Moreover, protein levels of Nrf2-ARE pathway-related factors were also examined using Western blot. Results SFN treatment could protect skeletal muscle against limb I/R injury, as evidenced by diminished inflammation, pyroptosis, autophagy, and oxidative stress in skeletal muscles of mice. Further mechanistic exploration confirmed that antioxidative protection of SFN was associated with the Nrf2-ARE pathway activation. Conclusions SFN activates the Nrf2-ARE pathway, and thereby inhibits pyroptosis and autophagy and provides a novel therapeutic strategy for the limb I/R-induced muscle tissue damage.

Farnesol-Loaded Nanoliposomes Inhibit Inflammatory Gene Expression in Primary Human Skeletal Myoblasts.

Simple SummaryObesity leads to the accumulation of free fatty acids (FFAs) and inflammation in skeletal muscle, which results in the loss of muscle mass and function. Farnesol is a natural hydrophobic compound from plants with poor bioavailability. We used a liposomal delivery system to direct farnesol into muscle cells and examined its possible beneficial effects on restraining inflammation. Our data strongly suggest that farnesol acts as a potent inhibitor of inflammatory gene expression in human myoblasts.There is a substantial unmet need for the treatment of skeletal muscle mass loss that is associated with aging and obesity-related increases in FFA. Unsaturated FFAs stimulate the inflammatory gene expression in human skeletal myoblasts (SkMs). Farnesol is a hydrophobic acyclic sesquiterpene alcohol with potential anti-inflammatory effects. Here, we created farnesol-loaded small unilamellar (SUVs) or multilamellar lipid-based vesicles (MLVs), and investigated their effects on inflammatory gene expression in primary human skeletal myoblasts. The attachment of SUVs or MLVs to SkMs was tracked using BODIPY, a fluorescent lipid dye. The data showed that farnesol-loaded SUVs reduced FFA-induced IL6 and LIF expression by 77% and 70% in SkMs, respectively. Farnesol-loaded MLVs were less potent in inhibiting FFA-induced IL6 and LIF expression. In all experiments, equal concentrations of free farnesol did not exert significant effects on SkMs. This report suggests that farnesol, if efficiently directed into myoblasts through liposomes, may curb FFA-induced inflammation in human skeletal muscle.

Mitochondrial Uncoupling Decreases Sarcopenic Obesity By Activation of Skeletal Muscle Mitochondrial Quality Control and Attenuated ER Stress

BackgroundSarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified an orally available mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 that selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.Methods80‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body composition, muscle function, energy expenditure, and locomotor activity were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signaling, and mitochondrial structure and function.ResultsBAM15 decreased body weight (~25% reduction, P&lt;0.001) which was attributable to increased energy expenditure (~20% increment, P&lt;0.001). BAM15 increased muscle mass (~13% increment, P&lt;0.001), strength (~37% increment, P&lt;0.0001), and locomotor activity (~25% increment, P&lt;0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (IL‐6 and gp130, both P&lt;0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis and reduced inflammation. Specifically, BAM15 activated mitochondrial quality control through AMPK (PINK1‐ubiquitin binding and LC3II, P&lt;0.01), increased electron transport chain activity (citrate synthase and complex II activity, all P&lt;0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P&lt;0.0001) while limiting ER stress (decreased PERK signaling, P&lt;0.0001), apoptotic signaling (decreased cytochrome C release and Caspase‐3/9 activation, all P&lt;0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P&lt;0.001).ConclusionsMitochondrial uncoupling agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity through activation of mitochondrial quality control and attenuation of ER stress.

Key contribution of NK cells to inflammation after muscle injury

Abstract Immune activation after tissue injury is required for removal of dead cells and debris to permit subsequent regenerative healing. Natural killer (NK) cells are innate lymphocytes that are essential for immune defense and for regulation of inflammation. NK cells limit fibrosis after cardiac muscle damage, yet the role of these cells during skeletal muscle inflammation is less clear. We hypothesize that NK cells promote acute inflammation after muscle damage but that NK cell responses must be resolved to permit regenerative healing. Following bilateral injection of cardiotoxin into tibialis anterior and gastrocnemius muscles of C57BL/6 mice, NK cell accumulation in injured muscle was detectable within 18 hours and peaked four days post-injury. Selective depletion of NK cells using a titrated dose of anti-NK1.1 antibody prior to cardiotoxin injection resulted in a substantial reduction in the overall infiltration of numerous immune cell types, including T and B cells, into the injured muscle. Thus, NK cells are an important mediator of cellular inflammation following muscle damage. Future studies will determine the mechanism by which NK cells contribute to this inflammatory response and how ablation of NK-cell mediated inflammation impacts healing of damaged muscles. Supported by National Institute of Heath (NIH) (R01-AI148080)

Lack of muscle stem cell proliferation and myocellular hypertrophy in sIBM patients following blood-flow restricted resistance training

Sporadic inclusion body myositis (sIBM) is characterised by skeletal muscle inflammation, progressive muscle loss and weakness, which is largely refractory to immunosuppressive treatment. Low-load blood-flow restricted (BFR) training has been shown to evoke gains in myofibre cross sectional area (mCSA) in healthy adults. This could partially be due to the activation and integration of muscle satellite cells (SC) resulting in myonuclei addition. Consequently, this study investigated the effect of 12-weeks lower limb low-load BFR resistance training in sIBM patients on SC and myonuclei content, myofibre size and capillarization. Muscle biopsies from sIBM patients randomised to 12-weeks of low-load BFR resistance training (n = 11) or non-exercising controls (CON) (n = 9) were analysed for SC and myonuclei content, myofibre size and capillarization using three-colour immunofluorescence microscopy and computerised quantification procedures. No between-group differences (time-by-group interactions) or within-groups changes were observed for resident SCs (Pax7+/Six1+), proliferating SCs (Pax7+/ Ki67+), myonuclei (Six1+), type 1 mCSA or capillary number (CD31+). However, a time-by-group interaction for type 2 mCSA was observed (p = 0.04). Satellite cell content, myonuclei number, mCSA and capillary density remained unaffected following 12-weeks low-load BFR resistance training, indicating limited myogenic capacity and satellite cell plasticity in long-term sIBM patients.

Capmatinib suppresses LPS-induced interaction between HUVECs and THP-1 monocytes through suppression of inflammatory responses

BackgroundCapmatinib (CAP) is a drug that has been used to treat non-small cell lung cancer (NSCLC) in adults. Presently, its novel effects on skeletal muscle insulin signaling, inflammation, and lipogenesis in adipocytes have been uncovered with a perspective of drug repositioning. However, the impact of CAP on LPS-mediated interaction between human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes has yet to be investigated. MethodsHUVECs and THP-1 monocytes were treated with LPS and CAP. The protein expression levels were determined using Western blotting. Target protein knockdown was conducted using small interfering (si) RNA transfection. Interactions between HUVECs and THP-1 cells were assayed using green fluorescent dye. ResultsThis study found that CAP treatment ameliorated cell adhesion between THP-1 monocytes and HUVECs and the expression of adhesive molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, phosphorylation of inflammatory markers, such as NFκB and IκB as well as TNFα and monocyte chemoattractant protein-1 (MCP-1) released from HUVECs and THP-1 monocytes, was prevented by CAP treatment. Treatment with CAP augmented PPARδ and IL-10 expression. siRNA-associated suppression of PPARδ and IL-10 abolished the effects of CAP on cell interaction between HUVECs and THP-1 cells and inflammatory responses. Further, PPARδ siRNA mitigated CAP-mediated induction of IL-10 expression. ConclusionThese findings imply that CAP improves inflamed endothelial-monocyte adhesion via a PPARδ/IL-10-dependent pathway. The current study provides in vitro evidence for a therapeutic approach for treating atherosclerosis.

P114 A service evaluation of the Myositis clinic at London North West University Healthcare Trust

Abstract Background/Aims The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare diseases, primarily characterised by inflammation of skeletal muscle which leads to muscle weakness, but often involving several other organ systems. The myositis service at London North West University Healthcare Trust (LNWUH) was created in 2017 with the aim of standardising care and improving clinical outcomes for patients. The International Myositis Assessment and Clinical Studies Group (IMACS) established disease activity core set measures to validate clinical response to treatment in studies, but the optimal treatment and real world data on clinical outcomes for patients with IIM is not well described. We undertook a service evaluation to understand the cohort, assess the effectiveness of the service, and in order to inform future service improvements for patients with IIM. Methods We performed a retrospective analysis of the IIM cohort at LNWUH as of January 2021, which consisted of 40 patients. Data were gathered from electronically stored notes and results. Results 65% of our cohort were female, 35% were male. The age range was 18-85. The most common subgroup was dermatomyositis (22.5%). The presenting symptoms included muscle weakness (82.5%), dysphagia (32.5%) and interstitial lung disease (ILD) (27.5%). The most common primary antibody was HMG-CoA reductase, followed by anti-Jo1. More than one antibody was present in 47.5% of patients. three patients had no detectable antibody. 1 in 5 patients had a normal creatine kinase (CK) at baseline. 89% had a raised troponin at baseline, with only two of these having confirmed cardiac involvement on imaging (echocardiogram or cardiac MRI). 30% of the cohort are currently taking mycophenolate mofetil (MMF), 27.5% are taking methotrexate, and 20% are taking hydroxychloroquine. 30% of patients have received rituximab, 20% intravenous immunoglobulin (IVIg), and 7.5% cyclophosphamide. Normalisation of CK was seen in 80% of patients, compared with 20% for pulmonary function tests (PFTs). 63% of patients were in clinical remission one year after diagnosis. Three patients died, two from MDA5-positive rapidly progressive interstitial lung disease. Conclusion In our cohort of patients with IIM, most patients had a significant improvement in their CK and muscle strength with treatment, but there remain challenges. We have established a baseline demographic and clinical outcome data for our cohort that will be used to make service improvements in line with the BSR guideline in development “Adult patients with idiopathic inflammatory myopathy”, and to assess future performance of the service. Disclosure I. Welding: None. A. Isaacs: None.

Sleeping With the Enemy? The Current Knowledge of Piscine Orthoreovirus (PRV) Immune Response Elicited to Counteract Infection.

Piscine orthoreovirus (PRV) is a virus in the genus Orthoreovirus of the Reoviridae family, first described in 2010 associated with Heart and Skeletal Muscle Inflammation (HSMI) in Atlantic salmon (Salmo salar). Three phases of PRV infection have been described, the early entry and dissemination, the acute dissemination phase, and the persistence phase. Depending on the PRV genotype and the host, infection can last for life. Mechanisms of immune response to PRV infection have been just beginning to be studied and the knowledge in this matter is here revised. PRV induces a classical antiviral immune response in experimental infection of salmonid erythrocytes, including transcriptional upregulation of ifn-α, rig-i, mx, and pkr. In addition, transcript upregulation of tcra, tcrb, cd2, il-2, cd4-1, ifn-γ, il-12, and il-18 has been observed in Atlantic salmon infected with PRV, indicating that PRV elicited a Th1 type response probably as a host defense strategy. The high expression levels of cd8a, cd8b, and granzyme-A in PRV-infected fish suggest a positive modulatory effect on the CTL-mediated immune response. This is consistent with PRV-dependent upregulation of the genes involved in antigen presentation, including MHC class I, transporters, and proteasome components. We also review the potential immune mechanisms associated with the persistence phenotype of PRV-infected fish and its consequence for the development of a secondary infection. In this scenario, the application of a vaccination strategy is an urgent and challenging task due to the emergence of this viral infection that threatens salmon farming.

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control.

BackgroundSarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.MethodsEighty‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.ResultsBAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1‐ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase‐3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P < 0.001).ConclusionsMitochondrial uncoupling by agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

Role of Exosomal miR-223 in Chronic Skeletal Muscle Inflammation.

As skeletal muscle is one of the largest organs in the body, its damage can directly reflect a decline in somatic function, thus, further affecting daily life and health. Inflammation is a prerequisite for the repair of injured skeletal muscles. Chronic inflammation induced by inadequate repair in skeletal muscle aggravates tissue injury. Exosomes regulate inflammatory responses to facilitate the repair of skeletal muscle injury. Moreover, exosomal miR‐223 with high specificity is the most abundant miRNA in peripheral blood and regarded as biomarkers for inflammation post skeletal muscle injury, which warrants further investigation. Available studies have demonstrated that exosomal miR‐223 negatively correlates with TNF‐α levels in serum and regulates the canonical inflammatory NF‐κB signaling pathway. miR‐223 is a negative feedback regulator with great potential for adjusting inflammatory imbalance and promoting skeletal muscle repair. The research on the regulation of negative feedback factors in the inflammatory signaling pathway is essential in biology and medicine. Therefore, this review mainly elaborates the formation, heterogeneity and markers of exosomes and points out exosomal miR‐223 as a beneficial role in chronic skeletal muscle inflammation and can be expected to be a potential therapeutic target for skeletal muscle damage.

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.