Skeletal Muscle Degeneration Research Articles

Prevalence and Socioeconomic Status of Patients with Genetic Myopathy in Korea: A Nationwide, Population-Based Study

Background: Genetic myopathy is a clinically and genetically heterogeneous group of genetic disorders characterized by progressive degeneration of skeletal muscles. Epidemiological studies of genetic myopathy have not yet been performed in Korea. Objectives: This study used data from the national health insurance claims database to determine the prevalence and socioeconomic status of patients with genetic myopathy in Korea. Methods: We analyzed the Health Insurance Review and Assessment database from 2007 to 2011. Patients with genetic myopathy were defined based on diagnostic and procedure codes. We then evaluated the prevalence, types of health insurances, and medical expenses of these patients. Results: During the 11-year study period, 2,988 patients with genetic myopathy were enrolled. Among them, 1,762 were men and 1,226 were women. The prevalence per 100,000 population in 2017 was 3.09 (3.94 for men and 2.24 for women). The prevalence of genetic myopathy among men <35 years old (8.33 per 100,000 population) was approximately twice that among women <35 years old (4.06 per 100,000 population). However, there was no significant difference in the prevalence of genetic myopathy among those ≥35 years old according to sex. The ratio of patients using medical aid among all genetic myopathy patients was approximately 4 times than that among the general population in Korea. The medical expenses per person for genetic myopathy increased from USD 2,027 in 2007 to USD 4,810 in 2017. Conclusions: Our study was the first nationwide epidemiologic study of the prevalence and socioeconomic status of patients with genetic myopathy in Korea. Our results confirmed a sex divergence in a younger population and those with low socioeconomic status among patients with genetic myopathy.

Open-Chamber Co-Culture Microdevices for Single-Cell Analysis of Skeletal Muscle Myotubes and Motor Neurons with Neuromuscular Junctions

Degeneration of motor neurons and skeletal muscles or the collapse of neuromuscular junctions (NMJs) causes progressive motility disturbances in many neuromuscular diseases. Although various microdevices for the co-culture of skeletal muscle myotubes and motor neurons have been developed to investigate neuromuscular diseases in vitro, it remains difficult to isolate single myotubes and motor neurons from the device for single-cell analyses, such as gene expression analysis. Here, we developed open chamber-coculture microdevices that contain cell culture chambers with narrow widths. Given the small chamber width (0.2 mm), the device significantly prevented the overlap among myotubes within the chamber. The percentage of non-overlapping was 95.6 ± 7.7% for the 0.2-mmwidth chamber and 11.8 ± 6.4% for the 7-mm-width chamber as a control. In addition, the device with the 0.2-mm chamber promoted myotube maturation, as indicated by the longer widths and lengths of the myotubes relative to those in the control chamber. Single C2C12 myotubes and human induced pluripotent stem cell (hiPSC)-derived motor neurons were successfully collected from the device with the 0.2-mm chamber using a micromanipulator equipped with a glass capillary. Furthermore, myotubes and hiPSC-derived motor neurons were co-cultured in the device with the 0.2- mm chamber, and the formation of NMJs were observed. Thus, the developed device is a useful tool for performing single-cell analysis for studying neuromuscular diseases in vitro.

MP25-20 EFFECT OF CHANGES IN SKELETAL MUSCLE MASS ON ONCOLOGICAL OUTCOMES DURING FIRST-LINE SUNITINIB THERAPY FOR METASTATIC RENAL CELL CARCINOMA

INTRODUCTION AND OBJECTIVES:Sarcopenia is a state of degenerative skeletal muscle wasting induced by cancer cachexia. To evaluate the prognostic impact of change in skeletal muscle mass (SMM) durin...

Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

Background:Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years.Objective:Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls.Methods:Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change.Results:FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P 0.004; and – 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P < 0.05, all comparisons).Conclusions:Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, andinhibiting Aurka blocks EGF stimulation-inducedasymmetric division. Invivo EGF treatment markedlyactivates asymmetric divisions of dystrophin-deficientsatellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating anEGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.

Acute AT1R blockade prevents isoproterenol-induced injury in mdx hearts

BackgroundDuchenne muscular dystrophy (DMD) is an X-linked disease characterized by skeletal muscle degeneration and a significant cardiomyopathy secondary to cardiomyocyte damage and myocardial loss. The molecular basis of DMD lies in the absence of the protein dystrophin, which plays critical roles in mechanical membrane integrity and protein localization at the sarcolemma. A popular mouse model of DMD is the mdx mouse, which lacks dystrophin and displays mild cardiac and skeletal pathology that can be exacerbated to advance the disease state. In clinical and pre-clinical studies of DMD, angiotensin signaling pathways have emerged as therapeutic targets due to their adverse influence on muscle remodeling and oxidative stress. Here we aim to establish a physiologically relevant cardiac injury model in the mdx mouse, and determine whether acute blockade of the angiotensin II type 1 receptor (AT1R) may be utilized for prevention of dystrophic injury. Methods and resultsA single IP injection of isoproterenol (Iso, 10 mg/kg) was used to induce cardiac stress and injury in mdx and wild type (C57Bl/10) mice. Mice were euthanized 8 h, 30 h, 1 week, or 1 month following the injection, and hearts were harvested for injury evaluation. At 8 and 30 h post-injury, mdx hearts showed 2.2-fold greater serum cTnI content and 3-fold more extensive injury than wild type hearts. Analysis of hearts 1 week and 1 month after injury revealed significantly higher fibrosis in mdx hearts, with a more robust and longer-lasting immune response compared to wild type hearts. In the 30-hour group, losartan treatment initiated 1 h before Iso injection protected dystrophic hearts from cardiac damage, reducing mdx acute injury area by 2.8-fold, without any significant effect on injury in wild type hearts. However, both wild type and dystrophic hearts showed a 2-fold reduction in the magnitude of the macrophage response to injury 30 h after Iso with losartan. ConclusionsThis work demonstrates that acute blockade of AT1R has the potential for robust injury prevention in a model of Iso-induced dystrophic heart injury. In addition to selectively limiting dystrophic cardiac damage, blocking AT1R may serve to limit the inflammatory nature of the immune response to injury in all hearts. Our findings strongly suggest that earlier adoption of angiotensin receptor blockers in DMD patients could limit myocardial damage and subsequent cardiomyopathy.

Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis.

Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.

Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutation of the DMD gene which encodes the protein dystrophin. This dystrophin defect leads to the progressive degeneration of skeletal and cardiac muscles. Currently, there is no effective therapy for this disorder. However, the technology of cell reprogramming, with subsequent controlled differentiation to skeletal muscle cells or cardiomyocytes, may provide a unique tool for the study, modeling, and treatment of Duchenne muscular dystrophy. In the present review, we describe current methods of induced pluripotent stem cell generation and discuss their implications for the study, modeling, and development of cell-based therapies for Duchenne muscular dystrophy.

Intoxicación por monensina en ovinos en Uruguay

Monensin is an antibiotic widely used in domestic animals. The aim of this paper is to describe three monensin poisoning outbreaks in sheep, occurred in 2015 and 2016, in the eastern region of Uruguay. The main clinical symptoms were anorexia, rigidity, hindlimb paresis, and finally lying sack. At necropsy the main findings were generalized subcutaneous edema, hydrothorax, hydroperitoneum and hydropericardium. In one case the urine had a reddish color. The hindlimb muscle masses showed pallor in all cases, while paleness in the heart muscle was observed in one case. The main histological lesions were degeneration and necrosis of skeletal and cardiac muscle. It is concluded that monensin poisoning in sheep occurs by the use of rations or salts formulated for cattle and by errors in commercial ration processing plants.

Proteomic profiling of liver tissue from the mdx-4cv mouse model of Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy is a highly complex multi-system disease caused by primary abnormalities in the membrane cytoskeletal protein dystrophin. Besides progressive skeletal muscle degeneration, this neuromuscular disorder is also associated with pathophysiological perturbations in many other organs including the liver. To determine potential proteome-wide alterations in liver tissue, we have used a comparative and mass spectrometry-based approach to study the dystrophic mdx-4cv mouse model of dystrophinopathy.MethodsThe comparative proteomic profiling of mdx-4cv versus wild type liver extracts was carried out with an Orbitrap Fusion Tribrid mass spectrometer. The distribution of identified liver proteins within protein families and potential protein interaction patterns were analysed by systems bioinformatics. Key findings on fatty acid binding proteins were confirmed by immunoblot analysis and immunofluorescence microscopy.ResultsThe proteomic analysis revealed changes in a variety of protein families, affecting especially fatty acid, carbohydrate and amino acid metabolism, biotransformation, the cellular stress response and ion handling in the mdx-4cv liver. Drastically increased protein species were identified as fatty acid binding protein FABP5, ferritin and calumenin. Decreased liver proteins included phosphoglycerate kinase, apolipoprotein and perilipin. The drastic change in FABP5 was independently verified by immunoblotting and immunofluorescence microscopy.ConclusionsThe proteomic results presented here indicate that the intricate and multifaceted pathogenesis of the mdx-4cv model of dystrophinopathy is associated with secondary alterations in the liver affecting especially fatty acid transportation. Since FABP5 levels were also shown to be elevated in serum from dystrophic mice, this protein might be a useful indicator for monitoring liver changes in X-linked muscular dystrophy.

Mitochondrial dysfunction and inhibition of myoblast differentiation in mice with high-fat-diet-induced pre-diabetes.

Pre-diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre-diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre-diabetes, in which 6-week-old male C57BL6/J mice were fed either normal diet or high-fat diet (HFD) for 8 or 16 weeks. Both non-fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8-week HFD developed pre-diabetes with IGT; whereas mice fed a 16-week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG-IGT). Mice at both stages of pre-diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG-IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG-IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid-induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre-diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage.

Voltage-Dependent Sarcolemmal Ion Channel Abnormalities in the Dystrophin-Deficient Heart.

Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. The current understanding of the pathomechanisms in the dystrophic heart is limited, but there is growing evidence that dysfunctional voltage-dependent ion channels in dystrophin-deficient cardiomyocytes play a significant role. Herein, we summarize the current knowledge about abnormalities in voltage-dependent sarcolemmal ion channel properties in the dystrophic heart, and discuss the potentially underlying mechanisms, as well as their pathophysiological relevance.

Effect of Changes in Skeletal Muscle Mass on Oncological Outcomes During First-Line Sunitinib Therapy for Metastatic Renal Cell Carcinoma.

Sarcopenia is a state of degenerative skeletal muscle wasting induced by cancer cachexia. To evaluate the prognostic impact of changes in skeletal muscle mass (SMM) during first-line sunitinib therapy on oncological outcomes in metastatic renal cell carcinoma (mRCC). Sixty-nine patients were evaluated retrospectively. The skeletal muscle index (SMI) was calculated based on computed tomography images obtained before the initiation (pre-treatment SMI) and after two cycles of sunitinib treatment (post-treatment SMI). The change in SMM was evaluated based on the value of ΔSMI, which was calculated as [(posttreatment SMI - pretreatment SMI)/ pretreatment SMI] × 100. Oncological outcomes were compared between patients with ΔSMI <0 (SMM decrease) and ΔSMI ≥0 (SMM maintenance). A decrease in SMM was observed in 38 patients (55.1%). Progression-free survival (PFS) and overall survival (OS) after sunitinib therapy initiation were significantly shorter in patients with ΔSMI <0 than in those with ΔSMI ≥0 (median PFS: 9.53 vs. 28.4months, p < 0.0001; OS: 19.8 vs. 52.6months, p = 0.0001). ΔSMI was an independent predictive factor for PFS (HR 3.25, 95% CI 1.74-6.29, p = 0.0002) and OS (HR 4.53, 95% CI 2.15-10.5, p < 0.0001). The objective response rate was significantly lower in patients with ΔSMI <0 than in those with ΔSMI ≥0 (23.7% vs. 51.6%, p = 0.0164). Decreased SMM during first-line sunitinib therapy can be aneffective markerof outcome prediction for mRCC.

STIM1 R304W causes muscle degeneration and impaired platelet activation in mice

STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

PO-098 Effect of HIIT on mitochondrial telomerase of skeletal muscle in aged rats

Objective The HIIT and moderate-intensity exercise are two different exercise models among the public fitness. In recent years, HIIT become more and more popular, unfortunately, there is a tremendous lack of research being done effects of mitochondrial reverse transcriptase (TERT) on age-related degeneration of skeletal muscle by HIIT. The purpose of this study was to compare the HIIT group and moderate-intensity group, and research difference of telomerase expression and cardiopulmonary endurance between the exercise group and the quiet control group was discussed.&#x0D; Methods fifty-nine male Wistar rats were divided into three groups at random: control group (Q=19), moderate-intensity intervention group (M=20), and HIIT intervention group (H=20). The rats in Q group did not any exercise, and the rats in M group developed the exercise with 60% VO2max intensity for 8 weeks. H group did a training program for an 8-week exercise with alternating 40%, 60%, and 80% VO2max intensities. The rats in the experimental group were exercised for 50 minutes every day and trained for 5 days per week. After the baseline value group was sampled, each group of rats was selected after the training reached the specified number of weeks (4 and 8 weeks), and the maximum oxygen uptake test was performed before the material was taken. Single factor analysis of variance were used to assess differences in VO2max, and expression of protein between conditions.&#x0D; Results It was found that H group VO2max was significantly higher than M group and Q group (P&lt;0.05). At same time, the mTERT expression of the M group at the 4th week was significantly higher than that of the Q group (P&lt;0.05). The mTERT expression in group H was significantly higher than that in group Q at week 8 (P&lt;0.05).There was no significant difference between the H group and the Q group at 8th week (P&lt;0.05).&#x0D; Conclusions 1. HIIT exercise lasting for 8 weeks can effectively inhibit the decrease of maximal oxygen uptake in aging rats compared with moderate exercise. 2. HIIT training for 8 weeks promotes the expression of mTERT; 3. The maintenance of VO2max in aging rats may be related to the enhancement of mitochondrial antioxidant function by HIIT-promoted TERT to mitochondrial translocation.

PO-084 Research of HIIT Detraining on Mitochondria of Soleus Muscle Beclin1 and Bnip3 Contents in Aging Rats

Objective To observe the temporal variation of Beclin1 and Bnip3 protein in skeletal muscle aging degeneration by constructing the aged rat model, and to observe the effect of HIIT intervention on the changes of Beclin1 and Bnip3 protein and the relationship between the two. It provides a theoretical basis for the effect of exercise on the aging degeneration of skeletal muscle by affecting the level of mitochondrial autophagy.&#x0D; Methods 40 male Wistar rats aged 8 months were randomly divided into quiet control group (C) and HIIT intervention group (H). After the rats entered the animal room for one week of adaptive feeding and exercise, the rats in the C group did not exercise, and the H group exercise alternately based on the maximum oxygen uptake test results of the rats with the 70%-90%-50%VO2max intensity. Once every two weeks, the maximal oxygen uptake of the rats in group H and group C was tested. Group H underwent 50min/ days, 5 days / weeks, and lasted for 16 weeks. The rats in the two groups were randomly selected after the first VO2 test and eighth and sixteenth weeks after intervention. After anesthesia, blood was collected from the abdominal aorta and soleus tissue was obtained. The ROS activity in soleus muscle was tested by fluorescence enzyme labeling method. Isolation of mitochondria from soleus muscle using tissue mitochondria Isolation Kit, and the expression of Beclin1 and Bnip3 in the mitochondria of the soleus muscle was tested by Western blot. The Image Lab 4 software was used to collect the data of the protein test strip, and the SPSS 17 software was used to analyze the data. The results of the data analysis were presented in the form of mean standard deviation. In the process of protein strip analysis, the relative value of the protein content of each sample was obtained by the gray scale analysis method. The results of the first sampling were taken as the baseline value, and the ratio of the H group in the C group of 8 weeks and 16 weeks was obtained with the baseline value, that is, the relative value of the protein content. Then, repeated measurement of variance analysis was used to analyze the differences of different indicators at baseline level, 8 weeks and 12 weeks between group C and group H. The independent sample T test was used without interaction effect, and multivariate analysis of variance was used. A significant level of alpha =0.05 is set.&#x0D; Results (1) the content of ROS in skeletal muscle of rats was related to the process of natural aging (F=119.314, P &lt; 0.001), and the level of ROS would rise with the process of natural collars (F=28.884, P=0.001; F=127.607, P &lt; 0.001) through the comparison of the time points in the group C and the H group. At the same time, the level of ROS in group H was lower than that in group C, but there was no significant difference (P=0.310). And the interaction effect of time and exercise mode (HIIT) will not affect the result (F=0.814, P=0.477). But the growth rate of ROS in group H was lower than that in C group. ⑵Exercise, time change and their interaction did not affect the content of Beclin1 in rat skeletal muscle mitochondria (P &gt; 0.05). ⑶The mitochondrial Bnip3 content in H group and C group was significantly different at 8 weeks (F=14.500, P=0.001), H group was significantly higher than that in C group, but there was no significant difference in mitochondrial Bnip3 content at the 16 week (F=0.090, P=0.767), and the Bnip3 content of skeletal muscle mitochondria changed with age (F=20.852, 0.001). The trend of H increased, but then decreased. There was a linear trend (F=6.950, P=0.005) between the level of mitochondrial Bnip3 content and the intergroup factors (time point changes) and the interaction between time and HIIT movement in rats.&#x0D; Conclusions With the process of aging, (1) The content of ROS in skeletal muscle of rats increased significantly, while long-term HIIT training could delay the increase, but the best exercise time was unknown. (2) There was no obvious change in Beclin1 content in skeletal muscle mitochondria of rats, and HIIT training had no obvious effect on it. However, the changes in mitochondrial Beclin1 content relative to the total Beclin1 content of skeletal muscle need to be further studied; (3) The content of Bnip3 in skeletal muscle mitochondria in rats is increased, and long-term HIIT training has a delayed effect.

EATING DISORDERS: A DISREGARDED RISK FOR CARDIAC ARREST

SESSION TITLE: Critical Care 5 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Eating disorders are associated with the highest mortality in among psychiatric illnesses. Severe and life threatening complications are due to self-induced vomiting, laxative or diuretic abuse. Most importantly, 80% of patients with eating disorders can develop cardiac complications including arrhythmias, QTc prolongation, and hypotension. We present a case of a young female patient with bulimia nervosa and profound hypokalemia, which resulted in cardiac arrest. CASE PRESENTATION: A 26 year-old female with history of bulimia nervosa, depression, anxiety, hypothyroidism, and PCOS presented status post cardiac arrest. Initial rhythm was ventricular fibrillation. She underwent defibrillation and a subsequent 30 minutes of CPR prior to ROSC. On presentation her BP was 94/72 mmHg with a MAP of 80 on 15 mcg of norepinephrine, HR of 108 bmp, RR of 33 bmp, temperature of 95 degrees Fahrenheit, and oxygen saturation of 100% mechanical ventilator. Significant labs included potassium of 1.7 mmoL/L, ABG with pH of 7.26, PCO2 of 43, PaO2 of 200, bicarbonate of 19 and arterial lactate of 26.6 mmoL/L. Urine drug screen and alcohol screen were negative. EKG revealed sinus tachycardia and QTc of 501 ms. Hemodynamic instability further deteriorated, thus, patient required additional vasopressor support. The patient was not a candidate for hypothermic protocol post cardiac arrest due to severe hypokalemia and refractory hypotension. She was started on Amiodarone and aggressive potassium replacement. Unfortunately, despite maximum efforts, the patient had another cardiac arrest and the family decided to withdraw care. DISCUSSION: Eating disorders (ED) are associated with increased risk of premature death. Hypokalemia occurs in approximately 14% of patients with bulimia nervosa leading to QTc prolongation, fatal cardiac arrhythmias, and degeneration of cardiac and skeletal muscle. The former is most commonly seen with levels less than 2.3 mmoL/L, which is a risk factor for development of torsade de pointes and ventricular fibrillation. Additionally, the QT interval is a measurement of myocardial repolarization and its prolongation can be a biomarker for ventricular tachyarrhythmia. Regrettably, these patients are not candidates for hypothermic protocols during cardiac arrests. Some studies, though, suggest use of ICD for prevention of sudden death. CONCLUSIONS: Bulimia nervosa is associated with severe complications secondary to vomiting, laxative, and diuretics use. It can commonly present with severe hypokalemia predisposing patients to cardiac arrhythmias and sudden death. Reference #1: Casiero D, Frishman W. Cardiovascular complications of eating disorders. Cardiology in Review 2006: Vol 14, number 5: 227-231. Reference #2: Jauregui-Garrido B, Jauregui-Lobera I. Sudden death in eating disorders. Vascular Health and Risk Management. 2012;8: 91-98. Reference #3: Beumont PJ, Russell JD, Touyz SW. Treatment of anorexia nervosa. Lancet. 1993;341:1635–1640. DISCLOSURES: no disclosure on file for Sam Copeland; No relevant relationships by Rocio Gavidia, source=Admin input No relevant relationships by Paloma Sanchez, source=Web Response

Targeting the Muscle-Bone Unit: Filling Two Needs with One Deed in the Treatment of Duchenne Muscular Dystrophy.

In Duchenne muscular dystrophy (DMD), the progressive skeletal and cardiac muscle dysfunction and degeneration is accompanied by low bone mineral density and bone fragility. Glucocorticoids, which remain the standard of care for patients with DMD, increase the risk of developing osteoporosis. The scope of this review emphasizes the mutual cohesion and common signaling pathways between bone and skeletal muscle in DMD. The muscle-bone interactions involve bone-derived osteokines, muscle-derived myokines, and dual-origin cytokines that trigger common signaling pathways leading to fibrosis, inflammation, or protein synthesis/degradation. In particular, the triad RANK/RANKL/OPG including receptor activator of NF-kB (RANK), its ligand (RANKL), along with osteoprotegerin (OPG), regulates bone matrix modeling and remodeling pathways and contributes to muscle pathophysiology in DMD. This review discusses the importance of the muscle-bone unit in DMD and covers recent research aimed at determining the muscle-bone interactions that may eventually lead to the development of multifunctional and effective drugs for treating muscle and bone disorders regardless of the underlying genetic mutations in DMD.

Predictive Tools and Databases for Toxicokinetics

Maduramicin, a polyether ionophore antibiotic used as an anticoccidial agent in poultry industry, has been reported to be toxic to animals and humans if improperly used or by accident, resulting in heart failure, skeletal muscle degeneration and even death. However, the molecular mechanism underlying its cardiotoxicity remains elusive. Mitogen activated protein kinases (MAPKs) and protein phosphatases signaling pathways have been documented to be involved in the cell survival regulation. The present study was set to investigate the role of above pathways in maduramicin-induced myocardial cytotoxicity. Here we observed that maduramicin inhibited cell proliferation and reduced cell viability in H9c2 cells. Furthermore, we found that maduramicin suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in a concentration-dependent manner. Ectopic expression of constitutively active MKK1 partially prevented the cytotoxicity of maduramicin. Moreover, we showed that maduramicin concentration-dependently activated protein phosphatase 2A (PP2A) by decreasing its phosphorylation and increasing its methylation. Inhibition of PP2A with okadaic acid attenuated maduramicin’s toxicity. Overexpression of dominant negative PP2A partially rescued cells from maduramicin-inhibited ERK1/2 contributing to its cytotoxicity. The results indicate that maduramicin activates PP2A and consequently inhibits ERK1/2, leading to cytotoxicity in H9c2 cells. Our data suggest that manipulation of PP2A-ERK1/2 pathway may be a potential approach to prevent maduramicin-induced cardiotoxicity.

Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice.

Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, results in chronic inflammation and irreversible skeletal muscle degeneration. Moreover, the associated impairment of autophagy greatly contributes to the aggravation of muscle damage. We explored the possibility of using non-euphoric compounds present in Cannabis sativa, cannabidiol (CBD), cannabidivarin (CBDV) and tetrahydrocannabidivarin (THCV), to reduce inflammation, restore functional autophagy and positively enhance muscle function in vivo. Using quantitative PCR, western blots and [Ca2+ ]i measurements, we explored the effects of CBD and CBDV on the differentiation of both murine and human skeletal muscle cells as well as their potential interaction with TRP channels. Male dystrophic mdx mice were injected i.p. with CBD or CBDV at different stages of the disease. After treatment, locomotor tests and biochemical analyses were used to evaluate their effects on inflammation and autophagy. CBD and CBDV promoted the differentiation of murine C2C12 myoblast cells into myotubes by increasing [Ca2+ ]i mostly via TRPV1 activation, an effect that undergoes rapid desensitization. In primary satellite cells and myoblasts isolated from healthy and/or DMD donors, not only CBD and CBDV but also THCV promoted myotube formation, in this case, mostly via TRPA1 activation. In mdx mice, CBD (60mg·kg-1 ) and CBDV (60mg·kg-1 ) prevented the loss of locomotor activity, reduced inflammation and restored autophagy. We provide new insights into plant cannabinoid interactions with TRP channels in skeletal muscle, highlighting a potential opportunity for novel co-adjuvant therapies to prevent muscle degeneration in DMD patients. This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.