Chronic Myopathy Research Articles

Chronic thyrotoxic myopathy development is associated with thyroid hormone sensitivity index, predicted by lower-limb fatigue and the squat-up test

Thyroid hormones (THs) may affect chronic thyrotoxic myopathy (CTM). The relationship between TH sensitivity and CTM is inconsistent. We aimed to investigate the associations between TH sensitivity and the risk of CTM and to screen potential CTMs with strength and function tests. A total of 162 Chinese patients (36.58% men) with Graves’ disease were enrolled and divided into CTM and non-CTM groups. TH and sensitivity indices were measured. Muscle power and function were assessed by grip, upper-limb fatigue (ULFT), lower-limb fatigue (LLFT), and squat-up (SUT) tests, and walking pace. Association between sensitivity to TH indices and the risk of developing CTM was assessed via multivariate logistic regression. The diagnostic effectiveness of muscle power and function for predicting CTM was evaluated via receiver operating characteristic (ROC) curves. Thyroid feedback quantile-based index FT3 (TFQIFT3) and the parametric TFQIFT3 (PTFQIFT3), TFQIFT4, and PTFQIFT4 were positively associated with CTM risk by using inverse probability of treatment weighting multivariate logistic regression. For each 1-SD increase in TFQIFT3 and PTFQIFT3, TFQIFT4 and PTFQIFT4, the odds ratios for CTM were 1.67 (95% CI = 1.17–2.48) ,1.64 (95% CI = 1.51–2.93), 1.60 (95%CI = 1.12–2.32), 1.58 (95%CI = 1.11–2.30), respectively. LLFT and SUT best predicted male/female CTM, respectively (AUC = 0.89/0.85). In Graves’ disease patients, TH sensitivity is associated with CTM development, which can be predicted by SUT and LLFT results.

Living with Pompe disease: results from a qualitative interview study with children and adolescents and their caregivers

BackgroundChildren and adolescents with Pompe disease (PD) face chronic and progressive myopathy requiring time-intensive enzyme replacement therapy (ERT). Little is known about their perspectives on the disease and its treatment. This study explored their perceptions of disease symptoms and functioning status, and more subjective feelings about the impacts on their lives as part of developing a disease-specific questionnaire.MethodsEleven pediatric patients aged 8–18 years and 26 caregivers from six children’s hospitals in Germany, Austria, and Switzerland underwent semi-structured interviews. Data were recorded, transcribed using MAXQDA software, and analyzed using qualitative content analysis. A system of meaningful categories was developed.ResultsSixteen main categories were derived across four major thematic areas: perceptions of symptoms and limitations, experiences to do with the biopsychosocial impact of PD, treatment experiences, and general emotional well-being/burden. Participants demonstrated broad heterogeneity in symptom perceptions such as muscle weakness, breathing difficulties, pain, and fatigue. Emotional appraisals of limitations were not directly proportional to their severity, and even comparatively minor impairments were often experienced as highly frustrating, particularly for social reasons. The main psychosocial topics were social exclusion vs. inclusion and experiences to do with having a disease. The main finding regarding treatment was that switching ERT from hospital to home was widely viewed as a huge relief, reducing the impact on daily life and the burden of infusions. Emotional well-being ranged from not burdened to very happy in most children and adolescents, including the most severely affected.ConclusionThis study provided qualitative insights into the perceptions and experiences of pediatric PD patients. Interestingly, biopsychosocial burden was not directly related to disease severity, and tailored psychosocial support could improve health-related quality of life. The present findings ensure the content validity of a novel questionnaire to be tested as a screening tool to identify patients in need of such support.

In Vivo Raman Spectroscopy of Muscle Is Highly Sensitive for Detection of Healthy Muscle and Highly Specific for Detection of Disease.

Raman spectroscopy of muscle provides a molecular fingerprint to identify the disease. Previous work has demonstrated effectiveness in differentiating between two groups of equal sizes (e.g., healthy vs disease) but imbalanced multiclass scenarios are more common in medicine. We performed in vivo Raman spectroscopy in a total of 151 mice across four different histopathologies (healthy, acute myopathy, chronic myopathy, neurogenic), with variable numbers in each (class "imbalance"). Using hierarchical modeling and synthetic data generation, we demonstrate high sensitivity (94%) for detection of healthy muscle and high specificity (≥97%) for disease. Further, we demonstrate the potential for unique biomarker development by demonstrating variations in the protein structure across different pathologies. The findings demonstrate the potential of Raman spectroscopy to provide accurate disease identification and unique molecular insights.

Clinical characteristics and prognostic factor in juvenile dermatomyositis: data of the Spanish registry

BackgroundJuvenile Dermatomyositis (JDM) is the most common chronic idiopathic inflammatory myopathy in children. The diagnosis is clinical. Baseline laboratory and complementary studies trace the phenotype of these patients. The objective of this study was to describe epidemiological, clinical and laboratory characteristics at diagnosis of JDM patients included in the Spanish JDM registry, as well as to identify prognostic factors on these patients.MethodsWe retrospectively reviewed clinical features, laboratory tests, and complementary studies at diagnosis of JDM patients included on the Spanish JDM registry. These data were analyzed to assess whether there was a relationship with the development of complications and time to disease inactivity.ResultsOne hundred and sixteen patients from 17 Spanish paediatric rheumatology centres were included, 76 girls (65%). Median age at diagnosis was 7.3 years (Interquartile range (IQR) 4.5–10.2). All patients had pathognomonic skin lesions at the beginning of the disease. Muscle weakness was present in 86.2%. Median Childhood Muscle Assessment Scale was 34 (IQR 22–47). Twelve patients (34%) had dysphagia and 3,5% dysphonia. Anti-p155 was the most frequently detected myositis specific antibody, followed by anti-MDA5. Twenty-nine patients developed calcinosis and 4 presented with macrophage activation syndrome. 70% reached inactivity in a median time of 8.9 months (IQR 4.5–34.8). 41% relapsed after a median time of 14.4 months (IQR 8.6–22.8) of inactivity. Shorter time to treatment was associated with better prognosis (Hazard ratio (HR) = 0.95 per month of evolution, p = 0.02). Heliotrope rash at diagnosis correlates with higher risk of development complications.ConclusionsWe describe heliotrope rash as a risk factor for developing complications in our cohort of JDM patients, an easy-to-evaluate clinical sign that could help us to identify the group of patients we should monitor closely for this complication.

Sarcoid Peripheral Neuropathy and Myopathy: A Diagnostic and Therapeutic Challenge

Sarcoidosis is an idiopathic granulomatous multi-organ disease, primarily affecting the respiratory system, eyes, and skin, with less involvement in peripheral neurons and muscles. Sarcoid peripheral neuropathy encompasses cranial and spinal nerve impairment. Muscle involvement is often asymptomatic and revealed through imaging. Symptomatic muscle involvement is categorized into three clinical types: nodular myopathy, acute myopathy, and chronic myopathy. The identification of noncaseating granulomas in peripheral nerves or muscles, coupled with the exclusion of other diseases, is essential for establishing a definitive diagnosis of sarcoid peripheral neuropathy and myopathy. Sarcoid neuropathy and myopathy are typically managed with high-dose corticosteroids, immunosuppressants, or a combination of both. In recent times, the use of TNF-alpha inhibitors has notably increased. However, these conditions often exhibit resistance to treatment and may necessitate prolonged therapeutic interventions. Therefore, comprehensive examinations should be conducted before considering immunotherapy. Due to the rarity of these conditions, research on manifestation-specific treatments is lacking, and standard treatments for sarcoid neuropathy and myopathy have not been established. Additional treatment options for sarcoid neuropathy and myopathy are expected to become available in the future.

The Diagnostic Value of Musculoskeletal Ultrasound in the Quantitative Evaluation of Skeletal Muscle in Chronic Thyrotoxic Myopathy: A Single-Center Study in China.

This study aimed to evaluate the quadriceps femoris in patients with chronic thyrotoxic myopathy (CTM) using musculoskeletal ultrasound and to explore its practical clinical value for the diagnosis of CTM. A total of 241 subjects recruited from the First Affiliated Hospital of Guangxi Medical University were surveyed for detailed medical history and underwent grip strength tests, fixed-distance walking, and quadriceps femoris ultrasound examinations. Differences in muscle parameters between the CTM, non-CTM, and healthy groups were analyzed. An Receiver operating characteristic (ROC) curve was established to analyze the predictive value of various ultrasound measurements for CTM, and Spearman correlation analysis and binary logistic regression were applied to explore the factors associated CTM. The quadriceps femoris contraction index, muscle thickness, muscle cross-sectional area, and pennation angle in the CTM group were significantly lower than those in the non-CTM and healthy groups (p<0.01). The ROC curve prediction showed that the pennation angle had the best sensitivity and specificity for diagnosing myogenesis, with an area under the curve of 89%. Moreover, the pennation angle of the CTM group was positively correlated with step speed (r=0.245, p=0.031) and body surface area (r=0.276, p=0.014), but negatively correlated with age (r=-0.306, p=0.007). Regression analysis showed that the quadriceps femoris contraction index, muscle thickness, pennation angle, and cross-sectional area were factors that related the CTM. After adjusting for potential confounding factors, the association between Muscle Bundle Length and CTM became significant (OR=1.99, 95% CI: 1.22, 3.35, p=0.007). Muscular echo in patients was observed to varying degrees of enhancement. Musculoskeletal ultrasonography in the quantitative analysis of muscle parameters and muscle echo of the quadriceps femoris can provide essential imaging evidence for predicting CTM.

GLOBAL HEALTH NEXUS: INTEGRATING AYURVEDA, YOGA AND PHYSIOTHERAPY MODALITIES

The contemporary field of medicine confronts formidable global challenges in addressing prevalent conditions such as tuberculosis, hemiplegia, AIDS, and cancer, with a persistent concern for the quality of life (QOL) among affected patients. Ayurveda, recognized as a holistic medical system, encompasses various parameters promoting good and healthy living. This includes a range of Panchakarma procedures, coupled with pre-Panchakarma interventions like Abhyang (oil massage), Swedana (sudation), Utsadana, and Mardana. The inclusion of yoga in the integrated approach expands the scope of treatment options available to individuals, offering a comprehensive framework that addresses the multifaceted dimensions of health and wellness.These therapies not only enhance muscular flexibility but also promote circulation and alleviate pain associated with conditions like chronic arthritis and myopathies.

Thyrotoxicosis: A rare cause of dysphagia

Excess and deficiency of thyroid hormones can have a variety of gastrointestinal manifestations ranging from heartburn, dysphagia, vomiting, diarrhea to constipation. We present a case of chronic thyrotoxic myopathy presenting as generalized weakness with bulbar involvement. He made a complete recovery with antithyroid therapy.

Current Biomarker Strategies in Autoimmune Neuromuscular Diseases.

Inflammatory neuromuscular disorders encompass a diverse group of immune-mediated diseases with varying clinical manifestations and treatment responses. The identification of specific biomarkers has the potential to provide valuable insights into disease pathogenesis, aid in accurate diagnosis, predict disease course, and monitor treatment efficacy. However, the rarity and heterogeneity of these disorders pose significant challenges in the identification and implementation of reliable biomarkers. Here, we aim to provide a comprehensive review of biomarkers currently established in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), and idiopathic inflammatory myopathy (IIM). It highlights the existing biomarkers in these disorders, including diagnostic, prognostic, predictive and monitoring biomarkers, while emphasizing the unmet need for additional specific biomarkers. The limitations and challenges associated with the current biomarkers are discussed, and the potential implications for disease management and personalized treatment strategies are explored. Collectively, biomarkers have the potential to improve the management of inflammatory neuromuscular disorders. However, novel strategies and further research are needed to establish clinically meaningful biomarkers.

Ultrasound measurement of vastus lateralis and vastus medialis muscle parameters to identify chronic thyrotoxic myopathy.

Chronic thyrotoxic myopathy (CTM) is a common, easily neglected complication of hyperthyroidism. There are currently no standard diagnostic criteria for CTM, and the ultrasonic characteristics of CTM-affected skeletal muscle remain unclear. Herein, we aimed to evaluate hyperthyroid patients for CTM by ultrasound and identify ultrasonic muscle parameter cutoffs for CTM diagnosis. Each participant underwent ultrasonography. The original (muscle thickness (MT), pennation angle (PA), and cross-sectional area (CSA)) and corrected (MT/height (HT), MT/body mass index (BMI), CSA/HT, and CSA/BMI) parameters of the vastus lateralis and vastus medialis (VM) were evaluated. The diagnostic effectiveness of ultrasound for predicting CTM was determined using receiver operating characteristic (ROC) curve analysis. Our study included 203 participants: 67 CTM patients (18 males, 49 females), 67 non-CTM patients (28 males, 39 females) and 69 healthy controls (20 males, 49 females). The CTM group had lower muscular ultrasonic and anthropometric parameters, higher thyroid hormone and thyroid-stimulating hormone receptor antibody (TRAb) levels, and a longer duration of hyperthyroidism than the non-CTM group (P < 0.05). The VM-PA, VM-CSA, VM-CSA/HT, and VM-CSA/BMI were lower in females than in males (P < 0.05). Free thyroxine (FT4) and TRAb both showed significant negative correlations with VM-MT, VM-MT/HT, VM-CSA, and VM-CSA/HT (P < 0.05). VM-MT/BMI and VM-CSA/HT, respectively, best predicted male and female CTM (AUC = 0.84, 0.85; cutoff ≤ 0.07, < 4.01). Ultrasound measurement of muscular parameters, especially in the VM, is a valid and feasible way of diagnosing and characterizing possible CTM in hyperthyroidism.

Increased serum soluble interleukin-2 receptor levels in dermatomyositis are associated with Th17/Treg immune imbalance.

Dermatomyositis (DM) represents a multifaceted chronic inflammatory myopathy, primarily manifesting as progressive deterioration of muscular and cutaneous tissues. Despite an incomplete comprehension of DM's etiology and pathogenesis, current evidence implicates the involvement of T lymphocyte infiltration, extensive cytokine release, myositis-specific antibodies, and myositis-associated antibodies in disease development. Serum soluble interleukin-2 receptor (sIL-2R) frequently serves as a marker for T cell activation; however, its role remains elusive. Consequently, this investigation sought to elucidate the association between sIL-2R levels, peripheral blood lymphocyte subset counts, and related cytokines in DM patients, with the aim of uncovering the intricate mechanisms underlying DM and establishing a theoretical foundation for the implementation of precise, targeted, individualized immunomodulatory therapy. In this study, a cohort of 60 dermatomyositis (DM) patients, comprising 32 with inactive DM and 28 with active DM, was enrolled and stratified into inactive and active groups based on the Myositis Disease Activity Visual Analogue Scale (MYOACT). Flow cytometry was employed to quantify the absolute counts of peripheral lymphocyte subsets and CD4+T cell subsets in each group, while a flow cytometry bead array was utilized to measure serum cytokine levels. In a comparative analysis between healthy individuals and patients diagnosed with DM, we observed a marked elevation in serum sIL-2R concentrations (P < 0.001) and T-helper 17 cell/regulatory T cell (Th17/Treg) ratios (P < 0.01) within the latter group. A positive correlation was identified between serum sIL-2R levels and various parameters, including ESR, CRP, VAS, AST, CKMB, LDH, HBDH, PT, APTT, DDi, IL-6, IL-10, and IFN-γlevels (P < 0.05). In contrast, serum sIL-2R levels demonstrated a negative correlation with LY, HGB, ALB, Th17 cell populations, and Th17/Treg cell ratios (P < 0.05). Employing multivariate logistic regression, we identified serum sIL-2R concentrations as an independent risk factor for both disease activity and hepatic involvement in DM patients. Moreover, receiver operating characteristic (ROC) curve analyses revealed that serum sIL-2R levels significantly contributed to the differentiation of disease activity and the detection of liver involvement in DM patients, with areas under the ROC curve (AUC) of 0.757 (95% CI 0.630-0.884, P = 0.001) and 0.826 (95% CI 0.717-0.935, P < 0.001), respectively. This study highlights the potential utility of serum sIL-2R levels as a valuable biomarker for assessing disease activity and liver involvement in dermatomyositis. Elevated serum concentrations of sIL-2R were observed in patients with DM, exhibiting significant associations with Th17 cell populations and Th17/ Treg ratios. These findings indicate that sIL-2R may be implicated in the immunopathogenesis of DM, thereby warranting further investigation to elucidate its role in the disease process.

Longitudinal assessment of strength and body composition in a mouse model of chronic alcohol-related myopathy.

Excessive, chronic alcohol consumption can result in muscle atrophy and weakness (i.e., alcoholic myopathy) that impairs the quality of life. However, the precise mechanisms responsible for ethanol's detrimental impact on skeletal muscle have not been fully elucidated, in part due because the time course of disease development and progression are not well established. Therefore, we examined muscle strength and body composition longitudinally using an established preclinical mouse model of chronic alcoholic myopathy. To establish a time course of chronic alcoholic myopathy, we fed High Drinking in the Dark (HDID) female mice (n = 7) 20% ethanol for ~32 weeks (following a 2-week ethanol ramping period). We assessed in vivo isometric contractility of the left ankle dorsiflexor and lean mass via NMR every 4 weeks. Outcomes were compared with age-matched control HDID mice that did not consume ethanol (n = 8). At study completion, mice who consumed ethanol were 12% weaker than control mice (p = 0.015). Compared to baseline, consuming ethanol resulted in an acute transient reduction in dorsiflexion torque at Week 4 (p = 0.032) that was followed by a second, more sustained reduction at Week 20 (p < 0.001). Changes in lean mass paralleled those of dorsiflexor torque, with ~40% of the variance in dorsiflexor torque being explained by the variance in lean mass of the ethanol group (p < 0.001). Dorsiflexor torque normalized to lean mass (mN·m/g lean mass) did not differ between the ethanol and control groups from Weeks 4 to 32 (p ≥ 0.498). These results indicate that reductions in muscle mass and strength due to chronic, excessive ethanol intake are dynamic, not necessarily linear, processes. Moreover, the findings confirm that ethanol-induced weakness is primarily driven by muscle atrophy (i.e., loss of muscle quantity). Future studies should consider how chronic alcoholic myopathy develops and progresses rather than identifying changes after it has been diagnosed.

Safety monitoring of drug-induced muscle injury and rhabdomyolysis: a biomarker-guided approach for clinical practice and drug trials.

Skeletal muscle tissue (SKM) may be damaged due to mechanical, metabolic, and exertional causes. However, drug-induced myopathy is among the most frequent causes of muscle disease. The clinical picture of drug-induced myopathies may be highly variable. It may present as asymptomatic or mild myalgias, with or without muscle weakness, which are likely underreported. However, it may also appear as chronic myopathy with severe weakness and, rarely, even as massive rhabdomyolysis with acute kidney injury (AKI). Unfortunately, the available biomarkers for SKM injury do not fully meet the needs for satisfactory detection of drug-induced damage, both in clinical and research settings, mainly due to their low sensitivity and specificity. Therefore, the present study proposes a strategy for drug safety monitoring using the available biomarkers of SKM injury. Moreover, we will discuss mechanisms of drug-induced SKM injury, traditional laboratory testing for SKM injury, and novel skeletal myocyte biomarkers under investigation. This can be incredibly useful in both clinical practice and for de-challenge/re-challenge investigational trials where the risk of drug-induced SKM injury is present.

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report

BackgroundNeutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen’s congenital myotonia.Case presentationWe describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan’s anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described.ConclusionsAlthough uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Delayed skeletal muscle repair following inflammatory damage in simulated agent-based models of muscle regeneration.

Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies.

Sarcoidosis, granulomas and myopathy syndromes: A clinical-pathology review

Muscle involvement in sarcoidosis is common by pathologic analysis, but symptomatic disorders are less frequent. Sarcoidosis-related muscle pathology includes non-caseating granulomas, muscle fiber changes that are diffuse or anatomically related to granulomas, and perimysial connective tissue with histiocyte-associated damage. The mechanisms by which granulomas form, enlarge and damage muscle tissues are incompletely understood. Sarcoidosis-related clinical syndromes with muscle involvement include: chronic myopathies with proximal weakness; nodular disorders; subacute onset disorders involving proximal or eye muscles; myalgia or fatigue syndromes; and, possibly, inclusion body myositis-like disorders. Corticosteroid treatment may benefit some syndromes, but clinical trials are necessary.

Neuromuscular mechanisms of weakness in a mouse model of chronic alcoholic myopathy.

Weakness is a common clinical symptom reported in individuals with chronic alcohol use disorder. However, it remains unclear whether low strength in these individuals is directly related to excessive ethanol intake, other deleterious factors (lifestyle, environment, genetics, etc.), or a combination of both. Therefore, we examined whether (and how) ethanol reduces the muscle's force-producing capacity using a controlled in vivo preclinical mouse model of excessive ethanol intake. To establish whether chronic ethanol consumption causes weakness, C57BL/6 female mice consumed 20% ethanol for 40 weeks (following a 2-week ethanol ramping period), and various measures of muscular force were quantified. Functional measures included all-limb grip strength and in vivo contractility of the left ankle dorsiflexors and plantarflexors. Once confirmed that mice consuming ethanol were weaker than age-matched controls, we sought to determine the potential neuromuscular mechanisms of muscle dysfunction by assessing neuromuscular excitation, muscle quantity, and muscle quality. Mice consuming chronic ethanol were 13 to 16% weaker (p≤ 0.016) than controls (i.e., mice consuming 100% water) with the negative impact of ethanol on voluntary grip strength(ƞ2 = 0.603) being slightly larger than that of electrically stimulated muscle contractility (ƞ2 = 0.482). Relative to controls, lean mass and muscle wet masses were 9 to 16% lower in ethanol-consuming mice (p≤ 0.048, ƞ2 ≥ 0.268). No significant changes were observed between groups for indices of neuromuscular excitation at the level of the motor unit, neuromuscular junction, or plasmalemma (p≥ 0.259, ƞ2 ≤ 0.097), nor was muscle quality altered after 40 weeks of 20% ethanol consumption (p≥ 0.695, ƞ2 ≤ 0.012). Together, these findings establish that chronic ethanol consumption in mice induces a substantial weakness in vivo that we interpret to be primarily due to muscle atrophy (i.e., reduced muscle quantity) and possibly, to a lesser degree, loss of central neural drive.

Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome.

Polymyositis (PM) is a chronic autoimmune inflammatory myopathy resulting in muscle weakness. The limited approved therapies and their poor efficacy contribute to its comorbidity. We investigated the therapeutic use of ONX 0914 and KZR-616, selective inhibitors of the immunoproteasome, in C protein-induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Diseased mice (day 13 postimmunization) were treated with 10 mg/kg ONX 0914, KZR-616, or vehicle on alternate days until day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity, histology, and immunohistochemistry analysis. Treatment with ONX 0914 or KZR-616 prevented the loss of grip strength in mice after CIM induction, while vehicle-treated animals displayed progressive muscle weakness. Immunoproteasome inhibition lowered PM-associated leukocyte infiltration of the muscle and prevented increased serum creatine kinase levels. LMP7-deficient mice were resistant to CIM induction, as they showed no alterations in grip strength or creatine kinase (CK) levels or muscular alterations. In conclusion, selective inhibition of the immunoproteasome displays therapeutic efficacy in a preclinical mouse model of PM with suppression of muscle inflammation and preservation of muscle strength. Positive results from this study support the rationale for using KZR-616 in clinical studies.

A 73-Year-Old Man with an Incidental Diagnosis of Deltoid Intramuscular Myxoma Following a History of Trauma

Patient: Male, 73-year-old Final Diagnosis: Intramuscular myxoma Symptoms: Shoulder pain Medication:— Clinical Procedure: — Specialty: General and Internal Medicine • Orthopedics and Traumatology Objective: Rare disease Background:Intramuscular myxomas are rare and benign soft-tissue tumors of uncertain differentiation. Predisposing or precipitating factors have not yet been reported. Activating mutation in GNAS (exons 8 and 9) is detected in >90% of sporadic cases. The role of chronic myopathy, tendinopathy, or trauma to muscles in the etiology of these neoplasms is not known. We report an unusual case of a deltoid mass found following longstanding rotator cuff tendinopathy and a recent fall, later confirmed to be an intramuscular myxoma on biopsy.Case Report:A 73-year-old man with a 5-year history of left shoulder pain and rotator cuff tear presented with intractable pain in his left shoulder after a recent fall at home. Physical examination was suggestive of a rotator cuff injury and magnetic resonance imaging (MRI) of the left shoulder revealed a 2.7×2.5×3.7cm T1 hypo- and T2 hyperin-tense oblong mass-like signal abnormality with heterogeneous, predominantly peripheral enhancement within the deltoid muscle concerning for a malignant mass. Surgical resection was carried out along with left reverse total shoulder replacement, and histopathology revealed findings consistent with an intramuscular myxoma.Conclusions:Intramuscular myxomas are rare, benign tumors. This case report presents one such myxoma incidentally found in a patient with longstanding rotator cuff tendinopathy and a recent fall. Although this co-occurrence is likely incidental, further research and case series review of similar presentations may influence postulations of the pathophysiology of myxomas.

Sirt2 positively regulates muscle regeneration after Notexin-induced muscle injury

Sirt2 regulates various biological processes by deacetylating target genes. Despite roles in regulating proliferation, cell cycle, and glucose metabolism, which are closely associated with skeletal muscle physiology, Sirt2 functions in this tissue remain unclear. In this study, genetic deletion of Sirt2 delayed muscle regeneration after Notexin-induced muscle injury. Gene expressions of myogenic regulatory factors, including Myf5, MyoD, and Myogenin, and cell cycle regulators, such as cyclin D1 and CDK2, were repressed in Sirt2 knockout mice after injury. Also, Sirt2 knockout mice presented muscle atrophy after muscle injury which is associated with the down-regulation of anabolic signaling and the up-regulation of catabolic signaling, in particular, increased atrogin1 transcriptional expression. Thus, Sirt2 positively regulated skeletal muscle regeneration after muscle injury by regulating transcriptional expression involved in myogenesis, cell cycle, and anabolic and catabolic signaling. Based on the in vivo analyses, Sirt2 could function as an interventional therapeutic for chronic myopathy, which is characterized by impaired muscle regeneration and muscle atrophy.