Skeletal Muscle Biomarkers Research Articles

Investigating skeletal muscle biomarkers for the early detection of Australian myotoxic snake envenoming: an animal model pilot study

Introduction Myotoxicity is an important toxidrome that can occur with envenoming from multiple Australian snake types. Early antivenom administration is an important strategy to reduce the incidence and severity of myotoxicity. The current gold standard biomarker, serum creatine kinase activity, does not rise early enough to facilitate early antivenom administration. Several other skeletal muscle biomarkers have shown promise in other animal models and scenarios. The aim of this study was to examine the predictive values of six skeletal muscle biomarkers in a rat model of Australian snake myotoxicity. Methods Sprague-Dawley rats were anaesthetised and administered either Pseudechis porphyriacus (red-bellied black snake) or Notechis scutatus (tiger snake) venom, or normal saline via intramuscular injection. Blood samples were collected. Assays were performed for serum creatine kinase skeletal muscle troponin-I concentration, skeletal muscle troponin-C concentration, myoglobin activity, skeletal muscle myosin light chain-1 concentration, and creatine kinase-MM activity. Serum markers were plotted against time, with comparison of area under the concentration (or activity)-time curve. The predictive values of six skeletal muscle biomarkers were examined using receiver operating characteristic curves. Results There was no difference in area under the serum creatine kinase activity-time curve between venom and control groups. Serum creatine kinase-MM activity rose early in the venom treated rats, which had a significantly greater area under the serum activity-time curve. No difference in area under the serum concentration-time curve was demonstrated for the other biomarkers. Creatine kinase-MM activity had a superior predictive values than creatine kinase activity at 0–4 hours and 0–10 hours after venom administration, as indicated by area under the receiver operating characteristic curves (95 per cent confidence intervals) of 0.91 (0.78–1.00) and 0.88 (0.73–1.00) versus 0.79 (0.63–0.95) and 0.66 (0.51–0.80). Discussion The limitations of serum creatine kinase activity in early detection of myotoxicity were demonstrated in this rat model. Conclusion Serum creatine kinase-MM activity was superior for early detection of Australian myotoxic snake envenoming.

Effect of HIF-1α inhibition with topotecan and postconditioning on cardiac and skeletal muscle biomarkers during severe hypoxia

The work used a model of severe hypobaric hypoxia (SH) – a three-hour session of rats staying at 180 mmHg (5% O2) and an attempt was made to evaluate the possibility of its use for muscle tissue by determining biomarkers of cardiac muscle and skeletal muscles damage in the blood plasma. To assess the effect of HIF1, we used the HIF-1α translation inhibitor, topotecan, which was administered intraperitoneally (5 mg/kg body weight) in a DMSO–0.09% NaCl mixture 10 min before hypoxia. For postconditioning (PostC), moderate hypobaric hypoxia was used [1]. A significant increase in the level of cardiac biomarker troponin I in the blood plasma of rats subjected to TH was shown, which indicated myocardial damage after SH. The blood level of the nonspecific muscle biomarker myoglobin did not change significantly after SH. However, when the HIF-1α inhibitor topotecan was used before SH, the amount of myoglobin in the blood plasma of rats one day after the SH session was significantly lower than in the absence of the inhibitor. Thus, it can be assumed that inhibition of the transcription factor HIF-1α before SH reduces skeletal muscle damage. Topotecan can be proposed as a means to reduce damage to injured muscles.

The effect of atorvastatin therapy on skeletal muscle function in hyperlipidemia patients in khartoum

Background: Atorvastatin is a lipid-lowering medication that causes skeletal muscle side effects by altering serum levels of skeletal muscle biomarkers. The aim of this study is to assess the effect of atorvastatin on muscle function and biomarker serum levels of CK, LDH, AST, Myoglobin, and Troponin I in Sudanese patients. Method: The total study group of hindered participants, including 60 case group (under Atorvastatin treatment) and 40 healthy as a control group, was matched with age and sex for the case group. The serum CK, LDH, myoglobin, and lipid profiles in the study groups were estimated by automated chemistry analyzers in this study. Result: Muscle pain was reported in case studies (55 = 91%). There was a significant increase in CK, LDH, and myoglobin among case studies when compared to the control group. The dose of drug showed no significant difference among the studied parameters. No correlation was found between CK and LDH with the duration of drug administration. Conclusion: Atorvastatin medication causes skeletal muscle pain among case study and increase muscle biomarkers such as CK, LDH, and myoglobin levels.

Assessment of Nutritional and Imaging Biomarkers to Predict PEG Tube Placement in Non-HPV-Associated Head and Neck Patients Undergoing Concurrent Chemoradiotherapy

<h3>Purpose/Objective(s)</h3> Patients with head and neck cancers undergoing chemoradiotherapy may require percutaneous endoscopic gastrostomy (PEG) tube placement because of dehydration or significant weight loss from their locally-advanced disease or treatment. Modifiable risk factors, such as sarcopenia, may identify high-risk populations who could benefit from intervention. Objective measures of sarcopenia include skeletal muscle index (SMI), skeletal muscle density (SMD), and skeletal muscle gauge (SMG), a novel measure which incorporates both SMI and SMD. We reviewed our institutional experience to assess pretreatment risk factors for nutritional deficiency with respect to serum and skeletal muscle biomarkers. <h3>Materials/Methods</h3> Definitive and post-operative patients undergoing concurrent chemoradiotherapy for locally advanced (AJCC 7^th edition Stage III-IVB) non-human papilloma virus (HPV)-associated head and neck cancer at an academic medical center between 2011 and 2016 were reviewed. Imaging analysis was assessed with three different skeletal muscle measures: SMI, SMD, and SMG. Measurements were obtained from radiation planning computed tomography scans by contouring muscles with an axial slice at the C3 vertebral body. Association between patient factors and PEG tube placement were calculated in univariate and multivariate analyses. <h3>Results</h3> A total 129 patients were included consisting of mostly males (91.5%) with primary tumors located in the larynx/hypopharynx (45.7%) and oropharynx (29.5%). Mean age was 62 years old (range 19-87) with a majority former or current smokers (80.6%) with ECOG performance status 0-1 (83.0%). 70% were treated with definitive chemoradiation and 30% were treated post-operatively. PEG tube was placed in 87/129 (67.4%) patients. Weight loss ≥10% was less common in patients with versus without PEG (30.0% vs 45.2%, p=0.086). Predictive factors on univariate analysis for PEG tube included older age (p=0.01), Caucasian race (p<0.01), former and current smoking status (p<0.01), low SMI (p=0.01), low SMD (p=0.04), deficiency of all 3 skeletal muscle measures (p<0.01), and low pretreatment albumin (p<0.01). On multivariate analysis, factors that persisted included Caucasian race (OR 5.13, p=0.01), current smoking status (OR 6.06, p<0.01), and low pretreatment albumin (OR 4.88, p<0.01). A receiver operating characteristic curve to estimate multivariate model sensitivity and specificity provided an area under the curve of 0.814 (95% CI, 0.738-0.890). <h3>Conclusion</h3> Pretreatment albumin level may serve as a predictive and modifiable pretreatment characteristic of head and neck patients receiving PEG tube placement for treatment. This evaluation identifies patients needing aggressive nutritional guidance, targeted supplementation, and early symptom management as a component of their care.

Do skeletal muscle composition and gene expression as well as acute exercise-induced serum adaptations in older adults depend on fitness status?

BackgroundInactive physical behavior among the elderly is one risk factor for cardiovascular disease, immobility and increased all-cause mortality. We aimed to answer the question whether or not circulating and skeletal muscle biomarkers are differentially expressed depending on fitness status in a group of elderly individuals.MethodsTwenty-eight elderly individuals (73.36 ± 5.46 years) participated in this exploratory study after participating as part of the multinational SITLESS-clinical trial (implementation of self-management and exercise programs over 16 weeks). A cardiopulmonary exercise test (CPX) and resting skeletal muscle biopsy were performed to determine individual physiological performance capacity. Participants were categorized into a high physical fitness group (HPF) and a low physical fitness group (LPF) depending on peak oxygen uptake (VO2peak). Serum blood samples were taken before (pre) and after (post) CPX and were examined regarding serum BDNF, HSP70, Kynurenine, Irisin and Il-6 concentrations. Skeletal muscle tissue was analyzed by silver staining to determine the myosin heavy chain (MyHC) composition and selected genes by qRT-PCR.ResultsHPF showed lower body weight and body fat, while skeletal muscle mass and oxygen uptake at the first ventilatory threshold (VO2T1) did not differ between groups. There were positive associations between VO2peak and VO2VT1 in HPF and LPF. MyHC isoform quantification revealed no differences between groups. qRT-PCR showed higher expression of BDNF and BRCA1 in LPF skeletal muscle while there were no differences in other examined genes regarding energy metabolism. Basal serum concentrations of Irisin were higher in HPF compared to LPF with a trend towards higher values in BDNF and HSP70 in HPF. Increases in Il-6 in both groups were observed post.ConclusionsAlthough no association between muscle composition/VO2peak with fitness status in older people was detected, higher basal Irisin serum levels in HPF revealed slightly beneficial molecular serum and muscle adaptations.Trial registrationClinicalTrials.gov, NCT02629666. Registered 19 November 2015.

The effect of vitamin D supplementation on serum total 25(OH) levels and biochemical markers of skeletal muscles in runners

BackgroundThe beneficial adaptation of skeletal muscle function to strenuous exercise is partially attributable to the improvement of vitamin D status. The present study aimed to evaluate the effects of a 3-week vitamin D supplementation on serum 25(OH)D levels and skeletal muscle biomarkers (i.e. troponin, myoglobin, creatine kinase and lactic dehydrogenase) of endurance runners.MethodsA double-blind placebo-controlled study design was used and vitamin D supplementation was compared to a non-treatment control group. Twenty-four runners, competitors of the ultra-marathons held during the National Running Championships, were randomly assigned into two groups supplemented with the dose of 2000 IU vitamin D or placebo for three weeks. All subjects participated in three exercise protocols: (a) incremental exercise test (to determine the maximum oxygen uptake and the intensity of eccentric exercise), (b) eccentric exercise before and (c) after two dietary protocols. Venous blood samples were drawn at rest, immediately after the exercise and after 1 h and 24 h of recovery in order to estimate serum 25(OH)D levels, skeletal muscle biomarkers, proinflammatory cytokines and tumor necrosis factor-alpha (TNF-α) levels. A two-way ANOVA was used to test main effects and their interactions and Pearson correlation coefficients were analyzed to determine the effects of inter-variable relationships.ResultsSignificant differences between pre- and post-intervention in baseline 25(OH)D levels were observed (34.9 ± 4.7 versus 40.3 ± 4.9 ng/ml, p = 0.02) in supplemented group. A higher post intervention 25(OH)D level was observed after vitamin D diet compared to placebo (40.3 ± 4.9 versus 31.8 ± 4.2 ng/mL, respectively; p < 0.05). The vitamin D supplementation decreased post-exercise (TN max) and 1 h post-exercise troponin (p = 0.004, p = 0.03, respectively), 1 h post-exercise myoglobin concentration (p = 0.01) and TNF-α levels(p < 0.03). 24 h post exercise creatine kinase activity was significantly lower in supplemented group compared to placebo (p < 0.05). A negative correlation was observed between post exercise 25(OH)D levels and myoglobin levels (r = − 0.57; p = 0.05), and 25(OH)D levels and TNFα (r = − 0.58; p = 0.05) in vitamin D supplemented group.ConclusionsThree weeks of vitamin D supplementation had a positive effect on serum 25(OH)D levels in endurance trained runners and it caused a marked decrease in post-exercise biomarkers levels. We concluded that vitamin D supplementation might play an important role in prevention of skeletal muscle injuries following exercise with eccentric muscle contraction in athletes.

Effect of ultramarathon race on liver and skeletal muscle biomarkers in recovery period

Effect of ultramarathon race on liver and skeletal muscle biomarkers in recovery period

Skeletal Muscle Toolbox.

Evaluation of skeletal muscle frequently combines morphologic and morphometric techniques. As is the case with many organ systems, skeletal muscle has limited responses to insult or injury. Over the past several years, crucial interactions between skeletal muscle, bone, and the nervous system have been described. The aim of this lecture was to give attendees the necessary background information in basic skeletal muscle morphology, important species differences, introduction to skeletal muscle biomarkers, approaches to morphologic and morphometric evaluation, and examples of background findings and typical responses of skeletal muscle to insult or injury.

Assessment of Preclinical Liver and Skeletal Muscle Biomarkers Following Clofibrate Administration in Wistar Rats

Clofibrate is a known rodent hepatotoxicant classically associated with hepatocellular hypertrophy and increased serum activities of cellular alanine aminotransferase/aspartate aminotransferase (ALT/AST) in the absence of microscopic hepatocellular degeneration. At toxic dose, clofibrate induces liver and skeletal muscle injury. The objective of this study was to assess novel liver and skeletal muscle biomarkers following clofibrate administration in Wistar rats at different dose levels for 7 days. In addition to classical biomarkers, liver injury was assessed by cytokeratin 18 (CK18) cleaved form, high-mobility group box 1, arginase 1 (ARG1), microRNA 122 (miR-122), and glutamate dehydrogenase. Skeletal muscle injury was evaluated with fatty acid binding protein 3 (Fabp3) and myosin light chain 3 (Myl3). Clofibrate-induced hepatocellular hypertrophy and skeletal muscle degeneration (type I rich muscles) were noted microscopically. CK, Fabp3, and Myl3 elevations correlated to myofiber degeneration. Fabp3 and Myl3 outperformed CK for detection of myofiber degeneration of minimal severity. miR-122 and ARG1 results were significantly correlated and indicated the absence of liver toxicity at low doses of clofibrate, despite increased ALT/AST activities. Moreover, combining classical and novel biomarkers (Fabp3, Myl3, ARG1, and miR-122) can be considered a valuable strategy for differentiating increased transaminases due to liver toxicity from skeletal muscle toxicity.

Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise.

The skeletal muscle (SKM) injury biomarkers, skeletal troponin I (sTnI), myosin light chain 3 (Myl3), and creatine kinase muscle isoform (Ckm) have been shown recently to be more sensitive and specific for monitoring drug-induced SKM injury than the conventional biomarkers, aspartate transaminase (AST) and creatine kinase (CK) enzymatic assays in rat toxicology studies. To evaluate the utility of these SKM biomarkers across species, they were assessed in 2 dog models: a drug-induced injury study in Beagle dogs and a 160 km endurance exercise run completed by Alaskan sled dogs. In the drug-induced injury model, mean sTnI and Myl3 plasma levels were 6- and 18-fold, respectively, compared with baseline as early as Study Day (SD) 15, while mean plasma AST and CK levels did not increase, and biopsy samples were non-remarkable for histopathology prior to SD 29 when degeneration was first noted. Peak group mean plasma responses over baseline for sTnI, Myl3, and Ckm biomarkers were 96-, 103-, and 11-fold, respectively, compared with 2.5-fold for AST and 3.8-fold for CK-enzymatic (CK-enz) assay. In the sled dog sustained exercise model, the peak response for all biomarkers was observed at the first sampling (2 h) after the completion of the run. The sTnI, Myl3, and Ckm mean fold peak values compared with baseline were 170-, 120-, and 150-fold, respectively, while AST increased 7-fold and CK-enz increased 29-fold. These findings support the conclusion that sTnI, Myl3, and Ckm are sensitive early tissue leakage biomarkers for monitoring SKM injury and effects of exercise in dog, extending their utility across preclinical species beyond the rat, and provide further support to investigate their translational utility to clinical trial settings to monitor for drug-induced SKM injury and ensure patient safety.

Evaluation of microRNAs − 208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats

Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague–Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48h. ISO, MET, and AAM induced cardiac and SKM lesions and APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity.

Biological and Analytical Variation of Clinical Biomarker Testing: Implications for Biomarker-guided Therapy

Testing for serum-based biomarkers are essential for diagnosis, risk stratification, and management of patients with cardiovascular disease. All biomarker assays have inherent analytical variability (coefficient of variance CVA), ranging from 5-20%. There are also variances within a subject over time (CVI) and between subjects (CVG). Variances are determined by experimentation under controlled conditions on healthy subjects. Once measured, the index of individuality (II), reference change value (RCV), and number of samples to establish a homeostatic set point can be calculated. These attributes affect how results of biomarker tests are interpreted in routine clinical practice such as cardiac troponin for acute coronary syndromes, the natriuretic peptides, galectin-3 and sST2 for heart failure, lipids and lipoproteins for primary cardiovascular disease risk, and liver function tests and skeletal muscle biomarkers for detecting complications from statin use.

Effects of acute exercise and xanthine oxidase inhibition on novel cardiovascular biomarkers

Several sports have been associated with a postexercise increase of cardiac, liver, and skeletal muscle biomarkers of injury. Exhaustive or acute physical exercise causes an increased generation of reactive oxygen species, resulting in cellular injury. Thus, exercise and training may trigger pathophysiological changes in serum concentrations of a variety of biomarkers. In this study, we aimed to evaluate the variation of novel biomarkers of stress and cardiovascular disease such as copeptin, midregional part of proadrenomedullin (MR-proADM), growth differentiation factor 15 (GDF15), soluble vascular endothelial growth factor receptor, and placental growth factor along with uric acid before and after acute high-intensity exercise and allopurinol administration. We also assessed whether allopurinol administration may affect the circulating levels of these biomarkers by inhibition of XO activity. This is a double-blind, placebo-controlled study in which 12 professional football players were divided into 2 experimental groups. An oral dose of 300 mg of allopurinol was administered to one group of six participants 4 hours before a match of the Spanish Football League, whereas the other 6 participants received placebo (cellulose). Venous blood samples were obtained before the match (baseline) and twelve hours afterwards (post-match). Serum MR-proADM levels increased significantly in the placebo group, whereas serum GDF15 levels increased significantly in both the placebo and allopurinol group after the match. No differences in the other parameters tested were found after the match in any experimental group. The trend toward postexercise increase of serum MR-proADM and GDF15 levels shows that the metabolism of these proteins is clearly imbalanced after exercise, which thereby represents a potential source of biological variability in their clinical assessment.

Skeletal Muscle Biomarkers in Heart Disease

On the other hand, methods on the market are nonstandardized, causing significantly different 99th percentile limits across the cTn assays [6]. Heterogeneity between assays is caused by the use of different antibodies for capture and detection of circulating cTn forms. A practical and convenient approach to deal with these differences has been proposed by Apple [6]. One of the factors taken into account in his scorecard for individual cTn assays is the analytical criterion recommended by the international guidelines, which requires a total imprecision equal to or less than 10% at the 99th percentile value [1,2]. Assays that are compatible with this requirement are designated as ‘guideline acceptable’. Using 20% as the maximal acceptable imprecision excludes a contemporary assay from clinical use, and assays with an imprecision between 10 and 20% are indicated as ‘clinically usable’ [6]. Another analytical issue that is important for clinical interpretation of cTn results is the impact of interferences. For example, human antimouse antibodies and rheumatoid factor cause falsely increased cTn, while anti-cTn autoantibodies cause falsely decreased cTn [7,8]. The influence of hemolysis appears to be method dependent, as it has been reported to increase cTnI on Vitros ECi (Ortho-Clinical Diagnostics) and to decrease cTnT on Roche instruments [9].

Skeletal muscle biomarkers: not new but still interesting diagnostic tools

Skeletal muscle biomarkers: not new but still interesting diagnostic tools