Serum Creatine Kinase Research Articles

Urinary titin in myotonic dystrophy type 1.

Urinary titin, an easy-to-obtain marker, has been investigated in muscular dystrophies, but not in myotonic dystrophy type 1 (DM1). We investigated the role of titin as a biomarker of muscle injury in DM1. We compared the urinary titin N-fragment/creatinine ratio in 29 patients with DM1 vs. 30 healthy controls. We also recorded clinical data such as muscle strength, serum creatine kinase, DM1-related outcome measures, and the 20-item DM1-activ questionnaire. The severity of the disease was graded using the Muscular Impairment Rating Scale (MIRS). The titin/creatinine ratio was significantly higher in the urine samples of DM1 patients than of healthy controls (median ± mean absolute deviation [MAD]: 39.313 ± 26.546 vs. 6.768 ± 5.245 pmol/mg creatinine; P < .001), and was related to muscle impairment graded by MIRS (τ = 0.503, P = .038). Urinary titin may be a biomarker for DM1. Long-term follow-up of DM1 patients is needed to investigate the potential role of titin as a biomarker for disease activity and progression.

Effect of Electroejaculation Protocols on Semen Quality and Concentrations of Testosterone, Cortisol, Malondialdehyde, and Creatine Kinase in Captive Bengal Tigers

The Bengal tiger (Panthera tigris tigris) is critically endangered, so assisted reproductive technologies, including artificial insemination, are important conservation tools. For wild and domestic felids, electroejaculation (EE) is the most common semen collection method, with protocols optimized to obtain sufficient amounts of viable sperm for artificial insemination. However, less attention has been paid to ensuring animal wellbeing during the process. This study examined the effects of three EE protocols (Low, 2–5 volts; Medium, 3–6 volts; High, 4–7 volts) on semen quality, testicular size, serum testosterone, creatine kinase (CK), and malondialdehyde (MDA) concentrations, and serum cortisol as a proxy for stress. Blood samples were collected before, during, and after each EE series. Seminal plasma pH, and sperm motility, viability, and morphology were evaluated after each procedure. Seminal plasma and sperm pellet MDA concentrations were also determined. Primary sperm abnormalities and seminal plasma MDA were higher in the Low compared to Medium and High voltage groups (p &lt; 0.05). Serum CK in the High voltage group increased during the EE series (p &lt; 0.05), suggesting the potential for muscle damage. However, no significant changes were observed for serum cortisol, testosterone, or MDA concentrations. Results suggest the Medium voltage protocol produced good quality samples at lower voltages than the High protocol with no negative effect on muscle function, which might be better for animal welfare.

Efficacy and muscle safety assessment of fukutin-related protein gene therapy

Limb-girdle muscular dystrophy type R9 (LGMDR9) is a muscle-wasting disease that begins in the hip and shoulder regions of the body. This disease is caused by mutations in fukutin-related protein (FKRP), a glycosyltransferase critical for maintaining muscle cell integrity. Here we investigated potential gene therapies for LGMDR9 containing an FKRP expression construct with untranslated region (UTR) modifications. Initial studies treated an aged dystrophic mouse model (FKRPP448L) with adeno-associated virus vector serotype 6 (AAV6). Grip strength improved in a dose- and time-dependent manner, injected mice exhibited fewer central nuclei and serum creatine kinase levels were 3- and 5-fold lower compared to those in non-injected FKRPP448L mice. Treatment also partially stabilized the respiratory pattern during exercise and improved treadmill running, partially protecting muscle from exercise-induced damage. Western blotting of C2C12 myotubes using a novel rabbit antibody confirmed heightened translation with the UTR modifications. We further explored the question of FKRP toxicity in wild-type mice using high doses of two additional muscle-tropic capsids: AAV9 and AAVMYO1. No toxic effects were detected with either therapeutic agent. These data further support the feasibility of gene therapy to treat LGMDR9.

The Effect of a Modified Mindfulness-Based Stress Reduction (MBSR) Program on Symptoms of Stress and Depression and on Saliva Cortisol and Serum Creatine Kinase among Male Wrestlers.

The aims of the present study were two-fold: to investigate whether, compared to an active control condition, a modified mindfulness-based stress reduction (MBSR) program could (1) reduce symptoms of stress and depression, and (2) regulate salivary cortisol and serum creatine kinase (CK) concentrations, two physiological stress markers. Thirty male wrestlers (Mage = 26.73 years) were randomly assigned either to the MBSR intervention or the active control condition. Both at the beginning and at the end of the intervention, the participants completed questionnaires on perceived stress and depression; in parallel, salivary samples were collected to measure cortisol in saliva, while blood samples were collected to assess serum CK. The study lasted for eight consecutive weeks. The intervention consisted of 16 group sessions (90 min each); the active control condition had an identical schedule, though without bona fide interventions. During the study period, the participants kept their sleeping, nutritional and exercising schedules unaltered. Over time, symptoms of stress and depression decreased; the level of decrease was more prominent in the MBSR condition than the active control condition (significant p values and large effect sizes of interaction). Further, cortisol and creatine kinase concentrations also decreased more in the MBSR condition compared to the active control condition (large effect sizes of interaction). The present study's findings suggest that among male wrestlers, a modified MBSR intervention have the potential to reduce both psychological (stress and depression) and physiological (cortisol and creatine kinase) indices as compared to an active control condition.

A retrospect study based on real-world data to observe metabolic function in cancer patients using albumin-bound paclitaxel

There is substantial evidence that albumin-bound paclitaxel (nab-paclitaxel) is effective and safe for the treatment of breast, lung and pancreatic cancers. However, it can still cause adverse effects by affecting cardiac enzymes, hepatic enzyme metabolism and blood routine related indicators, which affects the use of chemotherapy for a full course of treatment. However, there are no relevant clinical studies to systematically observe the effects and dynamics of albumin-bound paclitaxel on cardiac enzymes, liver enzyme metabolism, and routine blood-related indices. The purpose of our study was to determine the levels of serum creatinine (Cre), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), white blood cells (WBC) and hemoglobin (HGB) in cancer patients treated with albumin-conjugated paclitaxel. This study retrospectively analyzed 113 patients with cancer. Patients who had received two cycles of nab-paclitaxel 260 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle) were selected. Serum Cre, AST, ALT, LDH, CK, and CK-MB activities, WBC counts, and HGB levels were measured before and after treatment with two cycles. Fourteen cancer types were analyzed. The distribution of cancer types in patients was mainly concentrated in lung, ovarian, and breast cancer. Nab-paclitaxel treatment markedly decreased Cre, AST, LDH, and CK activities in the serum and WBC counts and HGB levels, respectively. Serum Cre and CK activities and HGB levels were remarkably downregulated at baseline compared to healthy controls. Patients receiving nab-paclitaxel treatment cause metabolic disorders in tumor patients by reducing the decrease of Cre, AST, LDH, CK, CK-MB, WBC and HGB indexes, thus inducing the occurrence of cardiovascular events, hepatotoxic events and fatigue and other symptoms. Therefore, for tumor patients, although receiving nab-paclitaxel improves the anti-tumor effect, it is still necessary to closely monitor the changes of related enzymatic and routine blood indicators, so as to detect and intervene at an early stage.

Risk Factors and Prognosis of Cardiovascular Damage in Hypereosinophilia

To investigate the risk factors and prognosis of cardiovascular damage in hypereosinophilia (HE). The clinical data of 62 patients with HE in Gansu Provincial Hospital from January 2015 to December 2020 were retrospectively analyzed, including clinical characteristics and laboratory indicators, and the influencing factors of survival and prognosis were also analyzed. In this study, there were 34 males and 28 females, with a median age of 53.5 (20-79) years, 35 patients without cardiovascular damage, 27 patients with cardiovascular damage, including 22 patients with abnormal electrocardiogram (ECG) (81.5%), 18 patients with abnormal echocardiography (ECHO) (66.7%), 9 patients with single ECG abnormality, 5 patients with single ECHO abnormality, and other 13 patients with multiple abnormalities. In cardiovascular damage group, peripheral white blood cell count, absolute value of eosinophils, troponin T (TNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin (IL)-4 and IL-5 levels at initial diagnosis were significantly higher than those in the non-cardiovascular damage group (P <0.01), while hemoglobin, IL-2 and interferon-γ levels were significantly lower (P <0.01). There were no significant differences in age, sex, course of disease, etiological classification, platelet count, serum creatine kinase, serum creatine kinase isoenzyme and lactate dehydrogenase between the two groups (P >0.05). The 5-year overal survival rate of patients with cardiovascular damage was 88.9%, and that of patients without cardiovascular damage was 100%, the difference was statistically significant (P =0.012). The 5-year event-free survival (EFS) rate of patients with cardiovascular damage was 59.3%, and the median time was 37 (21-52) months, while that of patients without cardiovascular damage was 80%, and the median time was 63 (51-74) months (P =0.002). Age (>60 years old), course of disease (>24 months), NT-proBNP (>3 000 pg/ml), TNT (>100 ng/L), elevated IL-4 and IL-5 were associated with EFS shortening in patients with cardiovascular damage, which were independent risk factors for EFS. The EFS rate in HE patients without cardiovascular damage is significantly higher than patients with cardiovascular damage. Age, course of disease, NT-proBNP, TNT, IL-4 and IL-5 are independent risk factors affecting EFS of patients with cardiovascular damage.

Nursing outcomes of traditional Chinese medicine adjunctive therapy on osteofascial compartment syndrome: a review†

Abstract The rate of disability due to acute osteofascial compartment syndrome (OCS) is high, and the therapeutic effect of decompressive fasciotomy is not ideal. This paper retrospectively reviews the modern treatment of OCS, including Western medicine and Traditional Chinese medicine (TCM), mainly in the context of the advantages of TCM in the treatment process of decompressive fasciotomy or conservative treatment to the patients who are suffering from OCS. It was found that TCM treatment reduced the levels of serum creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST); it is beneficial to the elimination of swelling and pain. TCM adjunctive therapy promotes patients’ postoperative functional recovery and decreases the occurrence of fasciotomy in patients; TCM can relieve tissue hypoxia of compartments and prevent necrosis of muscle and nerve tissue. TCM treatment improves the quality of medical service and ensures the safety of OCS patients. This paper aims to summarize the function of TCM in the treatment of OCS, provide reference for the clinical treatment of OCS, and improve the nursing/medical outcomes of OCS.

Associations of Serum CXCL12α and CK Levels with Skeletal Muscle Mass in Older Adults.

Sarcopenia, a condition characterized by gradual loss of skeletal muscle mass and function, is a complex diagnosis; the decisive criterion in this diagnosis is the measurement of appendicular skeletal muscle index (ASMI). To identify potential serum markers predictive of sarcopenia in older adults, we evaluated correlations between ASMI, clinical data, and 34 serum inflammation markers in 80 older adults. Pearson's correlation analyses confirmed that ASMI was positively correlated with nutritional status (p = 0.001) and serum creatine kinase (CK) (p = 0.019) but negatively correlated with serum CXCL12α (p = 0.023), a chemoattractant for muscle stem cells. In the case group, ASMI was negatively correlated with serum interleukin (IL)-7 (p = 0.024), a myokine expressed and secreted from skeletal muscle cells in vitro. Multivariate binary logistic regression analyses identified four risk factors for sarcopenia in our study: advanced age (p = 0.012), malnutrition (p = 0.038), low serum CK levels (p = 0.044), and high serum CXCL12α levels (p = 0.029). Low CK and high CXCL12α levels serve as combinatorial serum markers of sarcopenia in older adults. The linear correlation between ASMI and CXCL12α levels may facilitate the development of new regression models for future studies on sarcopenia.

Evaluation of the effect of oxidative stress on dynamics of cardiac biomarkers in Georgian elite athletes with overtraining syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background Training of professional athletes comprises of repetitive overloading to initiate structural and functional changes for favorable adaptation to the workouts, but with an inadequate recovery overloading may produce non-functional overreaching(NFO) and then overtraining syndrome(OTS). It is important to study chronic effects of exercises via responses of biomarkers for understanding of muscle fatigue and cardiac damage to identify athletes at risk of poor adaptation to training[3,4]. The purpose was to study the effects of oxidative stress on dynamics of cardiac biomarkers in Georgian elite athletes with OTS. Methods On the initial stage in 43 athletes(37 with NFO, 6 with OTS) study of relationship between oxidative stress and OTS revealed imbalance between oxidant production and antioxidant protection via attenuation of antioxidant capacity in athletes with OTS[1,2]. On the current stage of our study,in 43 NFO/OTS athletes and 40 age-matched controls without NFO/OTS pre-season serum creatine kinase myocardial band(CK-MB) and cardiac troponin I(cTnI) were measured, followed by in-season evaluation of the dynamic of their changes(HUMAN,Germany). In-season levels of CK-MB and cTnI were obtained 24hrs before strenuous sport-specific exercise of peak-season intensity, immediately after the work-load,after 6, 48,and 72hrs. Baseline and post-execise clinical assessment and transthoracic echocardiography(TTE) were performed in 6 and 48hrs after strenuous session(6 hrs corresponds to the time when cTnI is typically detectable in ischemic models;48 hrs-CK concentrations recovery time). Results Similar rising trend of CK-MB and cTnI levels was observed immediately after exercise, reaching peak values after 6hrs in all athletes, though, significantly greater in NFO/OTS athletes than in controls, and slightly exceeded reference range of cTnI (in NFO 0.128±0.092ng/ml, in OTS 0.137±0.061ng/ml). After 48hrs of recovery CK-MB and cTnI in NFO/OTS athletes were significantly higher than on entry, showing slower recovery,though normalized in 72hrs. TTE didn’t reveal any sustained alterations of systolic and diastolic functions, or clinically threatening myocardial damage, only minor diastolic changes due to adaptation to the post-exercise haemodynamic in OTS athletes(E/A pre-exercise:1.47±0.25, post-exercise:in 6hrs 1.06±0.14,in 48hrs 1.40±0.09,p&amp;lt;0,05). Elevated cardiac markers after strenuous exercise can be linked to increased cellular permeability and cardiac troponin leakage, amplified by oxidative stress existent in OTS athletes. Conclusions In our study intensive exercise caused transient increase of the CK-MB and cTnI in NFO/OTS athletes, without irreversible pathophysiological and clinical consequences, suggesting mostly benign cardiac involvement, though amplified by existent oxidative stress in athletes with OTS. Monitoring responses via alterations of biochemical parameters can be helpful to guide athletic training and prevent OTS.

Comparative Evaluation of Serum Urea, Uric Acid, and Creatine Kinase Levels in Oral Cancer and Potentially Malignant Disorders of the Oral Cavity: A Clinico-Biochemical Study.

Introduction Evidence suggests that oral potentially malignant disorders (OPMDs) are linked to increased possibilities of malignant transformation, creating a challenging situation.If oral cancer is detected early, the prognosis is better.The purpose of this study was to compare the serum levels of urea, uric acid (UA), and creatine kinase in patients with provisionally diagnosed and histopathologically confirmed cases of potentially malignant disorders and oral cancer to those of age- and sex-matched healthy controls. Materials and methods Eighty patients over the age of 18 with a clinical diagnosis of oral potentially malignant disorder (OPMD) or oral cancer and verified histopathology were included in the research. Using the kinetic methodology, the enzymatic colorimetric method, and the UV-kinetic approach, respectively, the serum concentrations of urea, uric acid, and creatine kinase were quantified in vitro following the venipuncture of 2 mL of venous blood. The Statistical Package for the Social Sciences (SPSS) version 20 (IBM SPSS Statistics, Armonk, NY, USA) was used for the statistical analysis. Results Comparing OPMD and oral cancer patients to healthy controls, serum urea levels were found to be greater, uric acid levels to be lower, and creatine kinase levels to be higher. Conclusion Prognostic markers for OPMDs and oral cancer may include urea, uric acid, and creatine kinase. However, this may be accomplished by large-scale prospective research.

Expanding the phenotypic spectrum of TRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant

BackgroundLimb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability.MethodsA clinical and histopathological characterisation...

The Effect of Short-term Administration of High-dose Vitamins E and C on Serum Creatine Kinase and Myoglobin in the Resting Phase of Elite Sanda Athletes: A Randomized Trial

Background: Muscle damage during continuous and intensive sports activities is common; therefore, experts in the field of sports medicine pay special attention to this issue. Objectives: We investigated the short-term effect of high-dose vitamin C and E supplements on serum levels of creatine kinase (CK) and myoglobin in elite athletes of the Sanda field. Methods: This research was a parallel single-blind randomized study design in which elite Sanda athletes were matched based on weight and randomly assigned to the vitamin C + E supplement (n = 10) and placebo groups (n = 10). Subjects took vitamin C (1400 U per day) and vitamin E (2000 U per day) supplements for 4 days (3 days before the competition and on the competition day). Blood sampling was done on the morning of the competition and 24 hours later (the following day) to measure serum levels of CK and myoglobin. Results: The serum CK level had a significant decrease in the supplement group (P = 0.001; mean ± SD: 237.2 ± 19.28), and myoglobin significantly increased (P = 0.001; mean ± SD, 41.1 ± 1.97) compared with the placebo group. Also, a paired sample t test showed that serum CK and myoglobin levels significantly decreased (P = 0.001; pretest, 307.7 ± 5.56; posttest, 237.2 ± 19.28) and increased (P = 0.005; pretest, 24.2 ± 2.7; posttest, 41.1 ± 1.97) in the supplement group, respectively, compared to the pretest values. However, no significant difference was observed in the placebo group. Conclusions: Short-term intake of high-dose vitamins C and E can facilitate recovery during competitive events such as Sanda. This claim can be defended based on the changes in CK and myoglobin in the blood serum of athletes.

B-Type Natriuretic Peptide Can Distinguish Ischemic Stroke Subtypes Better than Other Cardiac Biomarkers.

BACKGROUND The primary benefit to patients of being able to distinguish among subtypes of ischemic stroke (IS) is creation of a better treatment decision-making process. Current classification methods are complex and time-consuming, requiring hours to days. Blood-based cardiac biomarker measurements have the potential to improve mechanism classification of ischemic stroke. MATERIAL AND METHODS In this study, 223 patients with IS were selected as the case group and 75 healthy people who underwent physical examination at the same time were selected as the control group. The chemiluminescent immunoassay (CLIA) method established in this study was used to quantitatively detect plasma B-type natriuretic peptide (BNP) levels in subjects. All subjects were assessed for serum creatine kinase isoenzyme-MB (CK-MB), cardiac troponin I (cTnI), and myoglobin (MYO) after admission. We investigated the effectiveness of BNP and other cardiac biomarkers in the diagnosis of different subtypes of IS. RESULTS The levels of the 4 cardiac biomarkers were increased in IS patients. BNP could better diagnose different types of IS compared to other cardiac biomarkers, and BNP combined with other cardiac biomarkers was better than a single indicator in diagnosing IS. CONCLUSIONS Compared with other cardiac biomarkers, BNP is a better marker for the diagnosis of different subtypes of ischemic stroke. Routine screening for BNP in IS patients is recommended to improve the treatment decision-making process and minimize the time to thrombosis, thereby providing a more precise treatment for patients with different subtypes of stroke.

Expression of Myomaker and Myomerger in myofibers causes muscle pathology

BackgroundSkeletal muscle development and regeneration depend on cellular fusion of myogenic progenitors to generate multinucleated myofibers. These progenitors utilize two muscle-specific fusogens, Myomaker and Myomerger, which function by remodeling cell membranes to fuse to each other or to existing myofibers. Myomaker and Myomerger expression is restricted to differentiating progenitor cells as they are not detected in adult myofibers. However, Myomaker remains expressed in myofibers from mice with muscular dystrophy. Ablation of Myomaker from dystrophic myofibers results in reduced membrane damage, leading to a model where persistent fusogen expression in myofibers, in contrast to myoblasts, is harmful.MethodsDox-inducible transgenic mice were developed to ectopically express Myomaker or Myomerger in the myofiber compartment of skeletal muscle. We quantified indices of myofiber membrane damage, such as serum creatine kinase and IgM+ myofibers, and assessed general muscle histology, including central nucleation, myofiber size, and fibrosis.ResultsMyomaker or Myomerger expression in myofibers independently caused membrane damage at acute time points. This damage led to muscle pathology, manifesting with centrally nucleated myofibers and muscle atrophy. Dual expression of both Myomaker and Myomerger in myofibers exacerbated several aspects of muscle pathology compared to expression of either fusogen by itself.ConclusionsThese data reveal that while myofibers can tolerate some level of Myomaker and Myomerger, expression of a single fusogen above a threshold or co-expression of both fusogens is damaging to myofibers. These results explain the paradigm that their expression in myofibers can have deleterious consequences in muscle pathologies and highlight the need for their highly restricted expression during myogenesis and fusion.

1 Repeated muscle collections induce few physiological changes in mature sedentary horses

Repeated skeletal muscle collections are often used to determine tissue-specific responses to interventions or stressors but little is known about the physiological impacts of the collections themselves. Twenty-six mature sedentary horses (8 geldings, 18 mares; mean ± SD 9.5 ± 3.5y) were used to test the hypothesis that repeated muscle collections would not impact mitochondrial function or markers of inflammation and muscle damage. Horses were stratified by age and sex and randomly assigned to have gluteus medius samples collected at: 1) 0 and 24 h (n = 7); 2) 0 and 6 h (n = 6); 3) 0, 6, and 12 h (n = 7); or 4) 0, 6, 12, and 24 h (n = 6). Blood was collected from all horses every 6 h for 72 h total, starting 24 h before the first muscle collection. Muscle mitochondrial oxidative phosphorylation and electron transfer (E) capacities were determined via high-resolution respirometry, and mitochondrial volume density and function by citrate synthase (CS) and cytochrome c oxidase activities. Muscle and plasma concentrations of interleukin (IL)- 4, IL-8, IL-10, and tumor necrosis factor (TNF)α were quantified, as well as serum amyloid A (SAA) and cortisol concentrations and creatine kinase (CK) activity. Data were analyzed using linear models in SAS with time as a repeated measure, horse as the subject, time as a fixed effect, and sex when significant. For blood parameters, additional fixed effects includedcollection group and the time × group interaction. Integrative (per mg tissue) E supported by complex II decreased from 0 to 6 h (P = 0.004) but returned to baseline by 12 h post-initial muscle collection. Intrinsic (per unit CS) Leak was greater at 6 than at 0 and 12 h (P < 0.03) but did not differ from 24 h. Activity of CS was greater at 0 than 12 and 24 h (P ≤ 0.02). Regardless of group, serum CK activity was similar from −24 through 0 h but increased in all horses at 6 h and remained elevated through 48 h, peaking at 24 and 30 h post-initial muscle collection (P < 0.05). Geldings had greater serum CK activity and plasma IL-8 concentrations than mares (P ≤ 0.006). Serum cortisol concentrations displayed a circadian pattern throughout the 72-h collection period (P < 0.0001) but were not impacted by tissue collection group. Overall, horses in group 2 (0 and 6 h) had greater SAA concentrations than all other groups (P < 0.006). No other variable was impacted by repeated tissue collections. In unstressed, mature horses, repeated gluteal muscle collections did not profoundly impact local and systemic markers of mitochondrial function, select cytokines, and stress indicators; however, serum CK should be interpreted with caution in studies employing repeated tissue collections.

Becker Muscular Dystrophy Accompanied by Anti-HMGCR Antibody-positive Immune-mediated Necrotizing Myopathy.

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease characterized by progressive muscle weakness that currently has no cure. Immune-mediated necrotizing myopathy (IMNM) is a type of autoimmune inflammatory myopathy characterized by proximal muscle weakness that is treated with immunosuppressive therapy. We herein report a patient diagnosed with BMD complicated with IMNM by a pathological analysis. Notably, the patient had an elevated serum anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody level. Oral glucocorticoid and methotrexate treatment partially improved the muscle weakness with decreased levels of serum creatine kinase. An accurate diagnosis is important for therapeutic decisions in these complicated cases.

Lifelong Outcomes of Systemic Adeno-Associated Virus Micro-Dystrophin Gene Therapy in a Murine Duchenne Muscular Dystrophy Model.

Adeno-associated virus (AAV)-mediated systemic micro-dystrophin (μDys) therapy is currently in clinical trials. The hope is to permanently improve the life quality of Duchenne muscular dystrophy (DMD) patients. Numerous preclinical studies have been conducted to support these trials. However, none examined whether a single therapy at a young age can lead to lifelong disease amelioration. To address this critical question, we injected 1 × 1013 vg particles/mouse of an AAV serotype-9 μDys vector to 3-month-old mdx mice through the tail vein. Therapeutic outcomes were evaluated at the age of 11 months (adulthood, 8 months postinjection) and 21 months (terminal age, 18 months postinjection). Immunostaining and Western blot showed saturated supraphysiological levels of μDys expression in skeletal muscle and heart till the end of the study. Treatment significantly improved grip force and treadmill running, and significantly reduced the serum creatine kinase level at both time points. Since cardiac death is a major threat in late-stage patients, we evaluated cardiac electrophysiology and hemodynamics by ECG and the closed-chest cardiac catheter assay, respectively. Significant improvements were observed in these assays. Importantly, many ECG and hemodynamic parameters (heart rate, PR interval, QRS duration, QTc interval, end-diastolic/systolic volume, dP/dt max and min, max pressure, and ejection fraction) were completely normalized at 21 months of age. Our results have provided direct evidence that a single systemic AAV μDys therapy has the potential to provide lifelong benefits in the murine DMD model.

Irisin Alleviates Inflammatory Injury in Diabetic Cardiomyopathy by Regulating NF-κB Pathway

To investigate the protective effect of irisin in diabetic cardiomyopathy (DCM) and its mechanism. A mouse model of DCM was established by high-fat diet combined with the injection of streptozotocin. The mice were assigned to a control group, a DCM group, a DCM+low-dose irisin group, a DCM+high-dose irisin group, and a DCM+pyrrolidine dithiocarbamate (PDTC) (nuclear factor [NF]-κB inhibitor) group. Then, the mice received irisin intervention for 3 weeks after successful modeling. Myocardial morphologic changes were observed by hematoxylin and eosin (HE) staining and Masson staining. The levels of serum creatine kinase (CK) and creatine kinase isoenzyme CK-MB were examined by automatic biochemical analyzer. H9c2 cells were divided into the control group, high glucose and high lipid (HG/HL) group, HG/HL+low-dose irisin group, HG/HL+high-dose irisin group, and HG/HL+PDTC group. CCK-8 assay was conducted to determine cell viability. The expression levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in the myocardial tissue and the cells were determined by ELISA. In addition, nuclear translocation of NF-κB p65 protein and the protein expression level of NF-κB inhibitor protein α (IκBα) in the myocardial tissue and the cells were determined by Western blot. According to the results of animal experiment, low and high doses of irisin could alleviate the pathological injury and fibrosis of myocardial tissue to varying degrees. Irisin inhibited the levels of CK, CK-MB, and inflammatory factors, up-regulated IκB protein expression, and diminished NF-κB nuclear translocation. According to the results of cell experiment, low and high doses of irisin could enhance H9c2 cell viability to varying degrees, increase the level of intracellular IκB proteins, and inhibit NF-κB p65 nuclear translocation and inflammatory factor expression. The changes in these aspects in the DCM+low-dose irisin group and the DCM+high-dose irisin group were similar to those in the DCM+PDTC group. Through inhibiting NF-κB p65 nuclear translocation, irisin may reduce the inflammatory response in the myocardial tissue of DCM mice and H9c2 cells of myocardial injury induced by high glucose and high fat, thereby exerting a protective effect on myocardium.

Випадок мітохондріальної епізодичної міопатії (варіант без атрофії зорового нерва та оборотної лейкоенцефалопатії) у Прикарпатті

Mitochondrial episodic myopathy with/or without optic nerve atrophy and reversible leukoencephalopathy (MEOAL, OMIM 251900) belongs to rare primary mitochondrial myopathies, caused by nuclear genome DNA mutations with autosomal recessive inheritance. Purpose - to inform about the case of this current rare mitochondrial miopathy and encrease the knowledge of practical doctors in scope of diagnostics and treatment of the current orphan pathology Clinical case. In the clinical case being presented herein, the sick child had a severe course of the disease in the form of episodes of severe myopathy (during one of them there was a need for long-term mechanical lungventilation with the placement of a tracheostomy) in combination with severe metabolic crises. During crises, persistent keto- and lactic acidosis, a sharp increase in transaminases (alanine aminotransferase and aspartate aminotransferase) and creatine kinase in blood serum were observed. The patient did not have optic nerve atrophy or leukoencephalopathy. A similar course of the disease is described in the literature by different authors in only 3 cases. Molecular genetic analysis (Invitae laboratory, San Francisco) revealed 2 mutations of the FDX2 gene (the disease is associated with this gene) with uncertain pathogenic significance. Considering the presence of cardinal symptoms of MEOAL, this diagnosis was set to the patient, and therefore the detected mutations of the FDX2 gene should be considered as pathogenic. Conclusions. A thorough syndromic analysis of the phenotype together with a set of paraclinical examinations, including modern molecular genetic methods, made it possible to establish a clinical diagnosis of an extremely rare primary mitochondrial myopathy, which will contribute to further elucidation of relationships in the «genotype-phenotype» system and, possibly, reclassification of pathogenic genotypes in modern databases, as well as finding optimal approaches in treatment and rehabilitation of patients. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be an option for DMD patients. We focused on amnion-derived mesenchymal stromal cells (AMSCs), a clinically viable cell source owing to their unique characteristics, such as non-invasive isolation, mitotic stability, ethical acceptability, and minimal risk of immune reaction and cancer. We aimed to identify novel immunomodulatory effects of AMSCs on macrophage polarization and their transplantation strategies for the functional recovery of skeletal and cardiac muscles.MethodsWe used flow cytometry to analyze the expression of anti-inflammatory M2 macrophage markers on peripheral blood mononuclear cells (PBMCs) co-cultured with human AMSCs (hAMSCs). hAMSCs were intravenously injected into DMD model mice (mdx mice) to assess the safety and efficacy of therapeutic interventions. hAMSC-treated and untreated mdx mice were monitored using blood tests, histological examinations, spontaneous wheel-running activities, grip strength, and echocardiography.ResultshAMSCs induced M2 macrophage polarization in PBMCs via prostaglandin E2 production. After repeated systemic hAMSC injections, mdx mice exhibited a transient downregulation of serum creatin kinase. Limited mononuclear cell infiltration and a decreased number of centrally nucleated fibers were indicative of regenerated myofibers following degeneration, suggesting an improved histological appearance of the skeletal muscle of hAMSC-treated mdx mice. Upregulated M2 macrophages and altered cytokine/chemokine expressions were observed in the muscles of hAMSC-treated mdx mice. During long-term experiments, a significant decrease in the grip strength in control mdx mice significantly improved in the hAMSC-treated mdx mice. hAMSC-treated mdx mice maintained running activity and enhanced daily running distance. Notably, the treated mice could run longer distances per minute, indicating high running endurance. Left ventricular function in DMD mice improved in hAMSC-treated mdx mice.ConclusionsEarly systemic hAMSC administration in mdx mice ameliorated progressive phenotypes, including pathological inflammation and motor dysfunction, resulting in the long-term improvement of skeletal and cardiac muscle function. The therapeutic effects might be associated with the immunosuppressive properties of hAMSCs via M2 macrophage polarization. This treatment strategy could provide therapeutic benefits to DMD patients.