Muscle Myopathy Research Articles

Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients.

Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC.

Identification of circulating metabolites associated with wooden breast and white striping.

Current diagnostic methods for wooden breast and white striping, common breast muscle myopathies of modern commercial broiler chickens, rely on subjective examinations of the pectoralis major muscle, time-consuming microscopy, or expensive imaging technologies. Further research on these disorders would benefit from more quantitative and objective measures of disease severity that can be used in live birds. To this end, we utilized untargeted metabolomics alongside two statistical approaches to evaluate plasma metabolites associated with wooden breast and white striping in 250 male commercial broiler chickens. First, mixed linear modeling was employed to identify metabolites with a significant association with these muscle disorders and found 98 metabolites associated with wooden breast and 44 metabolites associated with white striping (q-value < 0.05). Second, a support vector machine was constructed using stepwise feature selection to determine the smallest subset of metabolites with the highest categorization accuracy for wooden breast. The final support vector machine achieved 94% accuracy using only 6 metabolites. The metabolite 3-methylhistidine, which is often used as an index of myofibrillar breakdown in skeletal muscle, was the top metabolite for both wooden breast and white striping in our mixed linear model and was also the metabolite with highest marginal prediction accuracy (82%) for wooden breast in our support vector machine. Overall, this study identified a candidate set of metabolites for an objective measure of wooden breast or white striping severity in live birds and expanded our understanding of these muscle disorders.

Abstract PR001: Oncogene-induced matrix reorganization controls CD8+ T cell immunity in the UPS microenvironment

Abstract CD8+ T cell dysfunction, characterized by reduced effector function, impaired proliferation, and inhibitory receptor upregulation, is a fundamental barrier to anti-tumor immunity. However, molecular mechanisms underlying the regulation of CD8+ T cell dysfunction in the tumor microenvironment (TME) are incompletely understood. In solid cancers, the extracellular matrix (ECM) facilitates tumor progression in part by inhibiting T cell migration/infiltration, but the impact of individual tumor-associated ECM molecules on T cell function remains unclear. Therefore, we investigated the regulation and impact of ECM composition on CD8+ T cell function in muscle-derived undifferentiated pleomorphic sarcoma (UPS). UPS exhibits durable responses to checkpoint therapy in a subset of human patients, potentially offering valuable insights into strategies for ameliorating T cell function and improving patient responses to immunotherapy. Using the autochthonous Kras G12D/+; Trp53 fl/fl (KP) murine model of UPS, we previously showed that deletion of the central Hippo pathway effector Yap1 (Kras G12D/+; Trp53 fl/fl; Yap1 fl/fl; KPY) suppressed UPS cell proliferation and tumor progression. Given the well-established role of Yap1 in mechanotransduction, we leveraged this system to investigate the effects of Yap1 on the ECM and CD8+ T cell function in UPS. We discovered that loss of UPS-cell intrinsic Yap1 reduced the proportion of dysfunctional CD8+ T cells in the TME and enhanced T cell cytolytic capacity. Yap1 loss also downregulated expression of multiple collagen genes in UPS cells and bulk tumors, including those that encode collagen type VI (ColVI). ColVI is a beaded microfilament collagen that binds to fibril-forming collagens in the ECM, such as collagen type I (ColI), and has been implicated in the pathogenesis of skeletal muscle myopathies. These data suggest that proper ColVI structure and function are critical for normal skeletal muscle physiology, with important implications for muscle-derived tumors such as UPS. Accordingly, COL6A1 was upregulated in human UPS relative to normal skeletal muscle, and inversely associated with UPS patient survival. Moreover, loss of UPS cell-intrinsic Col6a1 suppressed tumor progression, enhanced T cell cytolytic function, and attenuated CD8+ T cell exhaustion, phenocopying the effects of Yap1 deletion. Mechanistically, Yap1-mediated ColVI deposition promoted CD8+ T cell dysfunction by remodeling ColI networks in the UPS TME, and inhibiting T cell autophagic flux. Furthermore, ColI depletion dramatically increased tumor growth in an immunocompetent setting. Our findings reveal a novel role for UPS cell-intrinsic Yap1 in immune activation, and demonstrate that ColVI and ColI have opposing functions downstream of Yap in this context. These results underscore the need to systematically evaluate the roles of individual ECM components in the regulation of immune cell function, and implicate YAP1 and/or COLVI targeting as potential strategies for improving the efficacy of immunotherapy in human patients. Citation Format: Ashley M. Fuller, Hawley C. Pruitt, Hoogeun Song, Ying Liu, Ann Devine, Rohan S. Katti, Samir Devalaraja, Gabrielle E. Ciotti, Michael Gonzalez, Erik F. Williams, Ileana Murazzi, Nicolas Skuli, Hakon Hakonarson, Kristy Weber, Malay Haldar, Joseph A. Fraietta, Sharon Gerecht, T. S. Karin Eisinger-Mathason. Oncogene-induced matrix reorganization controls CD8+ T cell immunity in the UPS microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR001.

Comparison of incorporation of wild type and mutated actins into sarcomeres in skeletal muscle cells: A fluorescence recovery after photobleaching study.

The α-actin mutation G15R in the nucleotide-binding pocket of skeletal muscle, causes severe actin myopathy in human skeletal muscles. Expressed in cultured embryonic quail skeletal myotubes, YFP-G15R-α-actin incorporates in sarcomeres in a pattern indistinguishable from wildtype YFP-α-actin. However, patches of YFP-G15R-α-actin form, resembling those in patients. Analyses with FRAP of incorporation of YFP-G15R-α-actin showed major differences between fast-exchanging plus ends of overlapping actin filaments in Z-bands, versus slow exchanging ends of overlapping thin filaments in the middle of sarcomeres. Wildtype skeletal muscle YFP-α-actin shows a faster rate of incorporation at plus ends of F-actin than at their minus ends. Incorporation of YFP-G15R-α-actin molecules is reduced at plus ends, increased at minus ends. The same relationship of wildtype YFP-α-actin incorporation is seen in myofibrils treated with cytochalasin-D: decreased dynamics at plus ends, increased dynamics at minus ends, and F-actin aggregates. Speculation: imbalance of normal polarized assembly of F-actin creates excess monomers that form F-actin aggregates. Two other severe skeletal muscle YFP-α-actin mutations (H40Y and V163L) not in the nucleotide pocket do not affect actin dynamics, and lack F-actin aggregates. These results indicate that normal α-actin plus and minus end dynamics are needed to maintain actin filament stability, and avoid F-actin patches.

DEEP PECTORAL MYOPATHY IN BROILER CHICKEN OBTAINED FROM SUPERMARKET - CASE REPORT, LITERATURE REVIEW AND PREVENTIVE MEASURES

The fast growth rates in commercially reared chickens could lead to the changes in their muscle tissue structure and cause breast muscle myopathies, including deep pectoral myopathy (DPM). The incidence of DPM depends on various factors including rearing conditions, age, sex, weight and genetic strain. The aims of the present paper were to report a case of DPM in broiler chickens bought in a supermarket and review important information regarding this disease from the available literature, especially its effect on meat quality parameters and consumer preferences.

A conserved annexin A6-mediated membrane repair mechanism in muscle, heart, and nerve.

Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic modifier of muscle repair and muscular dystrophy. To evaluate annexin A6’s role in membrane repair in vivo, we inserted sequences encoding green fluorescent protein (GFP) into the last coding exon of Anxa6. Heterozygous Anxa6gfp mice expressed a normal pattern of annexin A6 with reduced annexin A6GFP mRNA and protein. High-resolution imaging of wounded muscle fibers showed annexin A6GFP rapidly formed a repair cap at the site of injury. Injured cardiomyocytes and neurons also displayed repair caps after wounding, highlighting annexin A6–mediated repair caps as a feature in multiple cell types. Using surface plasmon resonance, we showed recombinant annexin A6 bound phosphatidylserine-containing lipids in a Ca2+- and dose-dependent fashion with appreciable binding at approximately 50 μM Ca2+. Exogenously added recombinant annexin A6 localized to repair caps and improved muscle membrane repair capacity in a dose-dependent fashion without disrupting endogenous annexin A6 localization, indicating annexin A6 promotes repair from both intracellular and extracellular compartments. Thus, annexin A6 orchestrates repair in multiple cell types, and recombinant annexin A6 may be useful in additional chronic disorders beyond skeletal muscle myopathies.

Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study

IntroductionMalignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. ObjectiveTo assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. MethodsWe examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). ResultsMean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). ConclusionsPositive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

The Role of Incubation Conditions on the Regulation of Muscle Development and Meat Quality in Poultry.

Muscle is the most abundant edible tissue in table poultry, which serves as an important source of high protein for humans. Poultry myofiber originates in the early embryogenic stage, and the overall muscle fiber number is almost determined before hatching. Muscle development in the embryonic stage is critical to the posthatch muscle growth and final meat yield and quality. Incubation conditions including temperature, humidity, oxygen density, ventilation and lighting may substantially affect the number, shape and structure of the muscle fiber, which may produce long-lasting effect on the postnatal muscle growth and meat quality. Suboptimal incubation conditions can induce the onset of myopathies. Early exposure to suitable hatching conditions may modify the muscle histomorphology posthatch and the final muscle mass of the birds by regulating embryonic hormone levels and benefit the muscle cell activity. The elucidation of the muscle development at the embryonic stage would facilitate the modulation of poultry muscle quantity and meat quality. This review starts from the physical and biochemical characteristics of poultry myofiber formation, and brings together recent advances of incubation conditions on satellite cell migration, fiber development and transformation, and subsequent muscle myopathies and other meat quality defects. The underlying molecular and cellular mechanisms for the induced muscle growth and meat quality traits are also discussed. The future studies on the effects of external incubation conditions on the regulation of muscle cell proliferation and meat quality are suggested. This review may broaden our knowledge on the regulation of incubation conditions on poultry muscle development, and provide more informative decisions for hatchery in the selection of hatching parameter for pursuit of more large muscle size and superior meat quality.

Advances in the Treatment of Thyroid Eye Disease Associated Extraocular Muscle Myopathy and Optic Neuropathy.

To review emerging treatments for thyroid eye disease (TED) associated extraocular muscle myopathy and dysthyroid optic neuropathy (DON). Emerging targeted biologic therapies may alter the disease course in TED. Teprotumumab, a type I insulin-like growth factor receptor inhibitor, is the most recent addition to the treatments available for TED-associated extraocular muscle myopathy causing diplopia. Small studies also suggest a potential therapeutic benefit for DON. Various recent studies have also expanded our knowledge on conventional TED therapies. The therapeutic landscape of TED and its sequelae has evolved in recent years. New targeted therapies have the potential to reduce the extraocular muscle and orbital volume expansion which can lead to diplopia and vision loss from optic nerve compression. Longer term efficacy and durability data is needed to determine the role biologics, such as teprotumumab, should play in the treatment of TED patients compared to the current standard of care.

Interactions Between Statins, Exercise, and Health: A Clinical Update

Interactions Between Statins, Exercise, and Health: A Clinical Update

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

BackgroundMolecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored.MethodsWe performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates.ResultsHSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei.ConclusionsOur findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.

Use of retinoids in dermatology

Background: Retinoid, whose existence was first known in the 20th century, was initially referred to as a naturally occurring substance with vitamin A action. However, now it has become a generic term for all substances exhibiting an active action through the retinoid receptor located in the nucleus of the cells. Retinoids are biologically important substances involved in many functions, including reproduction, embryonic morphogenesis, regulation of epithelial proliferation and differentiation, reduction of sebaceous gland, immune and anti-inflammatory effects, tumor prevention, and effects on extracellular matrix components.Current Concepts: Topical retinoids are used to treat several conditions, including acne, photoaging, and psoriasis. Their side effects are dose-related skin irritations, while teratogenicity risk is rare to non-existent. Systemic retinoids are a treatment of choice for acne and keratinization disorders. They are also useful for the treatment of psoriasis, pityriasis rubra pilaris, cutaneous T-cell lymphoma, and chronic hand eczema. Systemic retinoid therapy requires the careful patient selection and monitoring due to associated teratogenicity. Other important side effects are hypertriglyceridemia, dryness of lips, blepharoconjunctivitis, bone pain, increased muscle tone, myopathy, hypothyroidism, and neutropenia.Discussion and Conclusion: Awareness of the side effects and proper use of retinoids are important for successful treatment outcomes of the above-mentioned dermatological conditions.

Reversal of diabetic-induced myopathy by swimming exercise in pregnant rats: a translational intervention study.

Gestational diabetes mellitus (GDM) plus rectus abdominis muscle (RAM) myopathy predicts long-term urinary incontinence (UI). Atrophic and stiff RAM are characteristics of diabetes-induced myopathy (DiM) in pregnant rats. This study aimed to determine whether swimming exercise (SE) has a therapeutic effect in mild hyperglycemic pregnant rats model. We hypothesized that SE training might help to reverse RAM DiM. Mild hyperglycemic pregnant rats model was obtained by a unique subcutaneous injection of 100 mg/kg streptozotocin (diabetic group) or citrate buffer (non-diabetic group) on the first day of life in Wistar female newborns. At 90 days of life, the rats are mated and randomly allocated to remain sedentary or subjected to a SE protocol. The SE protocol started at gestational day 0 and consisted of 60 min/day for 6 days/week in a period of 20 days in a swim tunnel. On day 21, rats were sacrificed, and RAM was collected and studied by picrosirius red, immunohistochemistry, and transmission electron microscopy. The SE protocol increased the fiber area and diameter, and the slow-twitch and fast-twitch fiber area and diameter in the diabetic exercised group, a finding was also seen in control sedentary animals. There was a decreased type I collagen but not type III collagen area and showed a similar type I/type III ratio compared with the control sedentary group. In conclusion, SE during pregnancy reversed the RAM DiM in pregnant rats. These findings may be a potential protocol to consider in patients with RAM damage caused by GDM.

The Impact of Resistance Exercise on Muscle Mass in Glioblastoma in Survivors (RESIST): Protocol for a Randomized Controlled Trial.

BackgroundGlioblastoma is the most common primary brain malignancy in adults, accounting for approximately 48% of all brain tumors. Standard treatment includes radiation and temozolomide chemotherapy. Glioblastomas are highly vascular and can cause vasogenic brain edema and mass effect, which can worsen the neurologic symptoms associated with the disease. The steroid dexamethasone (DEX) is the treatment of choice to reduce vasogenic edema and intracranial pressure associated with glioblastoma. However high-dose DEX or long-term use can result in muscle myopathy in 10%-60% of glioblastoma patients, significantly reducing functional fitness and quality of life (QOL). There is a wealth of evidence to support the use of exercise as an adjuvant therapy to improve functional ability as well as help manage treatment-related symptoms. Specifically, resistance training has been shown to increase muscle mass, strength, and functional fitness in aging adults and several cancer populations. Although studies are limited, research has shown that exercise is safe and feasible in glioblastoma populations. However, it is not clear whether resistance training can be successfully used in glioblastoma to prevent or mitigate steroid-induced muscle myopathy and associated loss of function.ObjectiveThe primary purpose of this study is to establish whether an individualized circuit-based program will reduce steroid-induced muscle myopathy, as indicated by maintained or improved functional fitness for patients on active treatment and receiving steroids.MethodsThis is a 2-armed, randomized controlled trial with repeated measures. We will recruit 38 adult (≥18 years) patients diagnosed with either primary or secondary glioblastoma who are scheduled to receive standard radiation and concurrent and adjuvant temozolomide chemotherapy postsurgical debulking and received any dose of DEX through the neurooncology clinic and the Nova Scotia Health Cancer Center. Patients will be randomly allocated to a standard of care waitlist control group or standard of care + circuit-based resistance training exercise group. The exercise group will receive a 12-week individualized, group and home-based exercise program. The control group will be advised to maintain an active lifestyle. The primary outcome, muscle myopathy (functional fitness), will be assessed using the Short Physical Performance Battery and hand grip strength. Secondary outcome measures will include body composition, cardiorespiratory fitness, physical activity, QOL, fatigue, and cognitive function. All measures will be assessed pre- and postintervention. Participant accrual, exercise adherence, and safety will be assessed throughout the study.ResultsThis study has been funded by the Canadian Cancer Society Atlantic Cancer Research Grant and the J.D. Irving Limited–Excellence in Cancer Research Fund (grant number 707182). The protocol was approved by the Nova Scotia Health and Acadia University’s Research Ethics Boards. Enrollment is anticipated to begin in March 2022.ConclusionsThis study will inform how individualized circuit-based resistance training may improve functional independence and overall QOL of glioblastoma patients.Trial RegistrationClinicalTrails.gov NCT05116137; https://www.clinicaltrials.gov/ct2/show/NCT05116137International Registered Report Identifier (IRRID)DERR1-10.2196/37709

Abstract 294: Heavy Alcohol Use Worsens Peripheral Artery Disease-Associated Myopathy

Heavy alcohol use can induce skeletal muscle dysfunction referred to as alcoholic myopathy. Likewise, peripheral artery disease (PAD) is characterized by an acquired skeletal muscle metabolic myopathy in ischemic muscles of the lower extremity. Although epidemiological studies have shown that heavy alcohol consumption is associated with a greater risk of PAD, data are lacking on the contribution of alcohol-related myopathy on PAD-associated skeletal muscle pathology. We compared myofiber morphometrics, mitochondrial respiration, and oxidative stress measures in gastrocnemius biopsies from PAD patients with heavy alcohol use (&gt;7 or &gt;14 drinks per week, for females and males, respectively) (n=13) to PAD patients (n=13) and non-PAD controls (n=17) consuming moderate to low/no alcohol. Myofiber area and diameter were lower in heavy-drinking PAD patients compared to low/moderate drinkers (p=0.03 and p=0.04, respectively) and non-PAD controls (p=0.02 and p&lt;0.001, respectively). Myofiber roundness was significantly higher in heavy-drinking PAD patients compared to low/moderate drinkers (p=0.04) and non-PAD controls (p&lt;0.001). Although there were no significant differences between PAD groups in mitochondrial respiration, PAD patients with heavy alcohol consumption tended to have lower respiration for Complex I (p=0.14), Complex II (p=0.10), and Complex IV (p=0.16) compared to PAD patients without heavy alcohol use. Both PAD groups had significantly reduced respiration of all Complexes compared to non-PAD controls (p&lt;0.05). These data suggest that alcohol abuse may accentuate skeletal muscle pathology in PAD patients.

Prevalence of breast muscle myopathies (spaghetti meat, woody breast, white striping) and associated risk factors in broiler chickens from Ontario Canada.

Spaghetti meat (SM), woody breast (WB), and white striping (WS) are myopathies that affect the pectoral muscle of fast-growing broiler chickens. The prevalence and possible risk factors of these myopathies have been reported in other countries, but not yet in Canada. Thus, the objective of this study was to assess the prevalence and risk factors associated with these myopathies in a representative population of Canadian broilers. From May 2019 to March 2020, 250 random breast fillets from each of 37 flocks (total, 9,250) were obtained from two processing plants and assessed for the presence and severity of myopathies. Demographic data (e.g., sex and average live weight), environmental conditions during the grow-out period (e.g., temperature), and husbandry parameters (e.g., vaccination) were collected for each flock. Associations between these factors and the myopathies were tested using logistic regression analyses. The prevalence of SM, severe WB, and mild or moderate WS was 36.3% (95% CI: 35.3–37.3), 11.8% (95% CI: 11.2–12.5), and 96.0% (95% CI: 95.6–96.4), respectively. Most (85.1%) of the fillets showed multiple myopathies. Regression analyses showed that the odds of SM increased with live weight (OR = 1.30, 95% CI 1.01–1.69) and higher environmental temperature during the grow-out period (OR = 1.75, 95% CI 1.31–2.34). The odds of WB increased with live weight (OR = 1.23, 95% CI 1.03–1.47) and when flocks were not vaccinated against coccidia (OR = 1.86, 95% CI 1.51–2.29). This study documents for the first time a high prevalence of myopathies in Ontario broilers, and suggests that these lesions may have a significant economic impact on the Canadian poultry industry. Our results indicate that environmental conditions and husbandry are associated with the development of breast myopathies, in agreement with the current literature. Future studies are needed to determine how risk factors can promote the occurrence of these conditions, in order to implement possible mitigating strategies.

Breast muscle myopathies in broiler: mechanism, status and their impact on meat quality – A review

Abstract Almost a decade ago, the sudden rise of breast muscle defects in fast-growing commercial broiler breeds challenged the broiler production industry and meat scientists to address the issue of these novel muscle abnormalities. After that, a widespread hypothesis showing a correlation between high muscle yield and incidence of these muscle myopathies received much acceptance from the research community. Increased muscle hypertrophy and unbalanced growth of connective tissues lead to an inadequate blood supply that ultimately causes hypoxia in muscle fibers. Reduced blood vascular density in muscle fibers induces oxidative stress and mitochondrial dysfunction, leading to muscle fibrosis, lipidosis and myodegeneration. Along with physical changes, the myopathic muscles exhibit poor sensory properties, abnormal texture properties and a low nutritional profile. As these myopathies alter meat’s physical appearance, they have a negative impact on customer’s behavior and preference. A better production environment with proper dietary supplementation with balanced breeding strategies can minimize the incidence of muscle myopathies in broiler chicken. This review aims to address the underlying mechanism behind these myopathies and their impact on poultry meat quality, including nutritional value and consumer behavior. It describes the link between genetic and non-genetic elements influencing myopathies, along with the strategies to minimize the occurrence of breast muscle myopathies.

Thyroid Storm Presenting with Isolated Acute Bulbar Myopathy: A Case Report and Literature Review

AbstractWhile proximal skeletal muscle myopathy is a frequently reported complication of thyrotoxicosis, acute bulbar thyrotoxic myopathy is rare especially in absence of other forms of myopathy. In this report, we present a case of 31 years old male presenting with thyrotoxicosis and aspiration pneumonia following weeks of experiencing dysphagia and hoarseness of voice. Labs confirmed Graves' disease and other causes of bulbar myopathy like Myasthenia gravis was ruled out. He was started on thyroid treatment and showed remarkable improvement of dysphagia over 15 days. Based on this, we conclude that isolated bulbar myopathy in hyperthyroidism should be considered in patients presenting with dysphagia and dysphonia in absence of other possible neurological causes.

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility.

BackgroundAbout half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so‐called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed‐205) in HFpEF and to describe molecular changes elicited by MyoMed‐205.MethodsTwenty‐week‐old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed‐205 for 12 weeks; a comparison was made to age‐matched untreated ZSF1‐lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome‐wide analysis followed by WBs and RT‐PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1‐KO) SKM tissues were included to validate MuRF1‐specificity.ResultsBy week 32, untreated obese rats had normal LV ejection fraction but augmented E/e′ ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed‐205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed‐205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed‐205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed‐205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1‐KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.ConclusionsMyoMed‐205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.

Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.

Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient’s muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient’s clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient’s fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.