Search Results (915)

The rapid growth of broiler production efficiencies has been driven by selective breeding and optimized nutrition. However, these advancements have also introduced muscle myopathies such as wooden breast (WB), white striping (WS), and spaghetti meat (SM), which impair meat quality and cause major economic losses for the broiler industry. This review summarizes myopathy etiology, structural and physiological changes, detection methods, and mitigation strategies. It discusses factors such as accelerated muscle growth, poor circulation, oxidative stress, and metabolic imbalance, along with impacts on meat quality and industry economics. Current detection approaches range from visual and tactile assessments to advanced technologies like near-infrared spectroscopy and computer vision. Nutritional interventions have been evaluated as strategies to reduce the incidence of myopathies. The review emphasizes the need for further research to clarify underlying mechanisms and develop effective prevention and detection solutions. Full article

Store-operated Calcium (Ca²⁺) entry (SOCE), mediated by stromal interaction molecule 1 (STIM1) and Orai1, is a central pathway controlling intracellular Ca²⁺ homeostasis. Gain-of-function (GoF) mutations in STIM1 cause a spectrum of clinically overlapping disorders historically classified as Stormorken Syndrome (STK), tubular aggregate myopathy (TAM), and York Platelet Syndrome (YPS). However, increasing evidence indicates that these entities could represent a shared disease spectrum rather than distinct conditions. At the molecular level, STIM1 activation is governed by a series of autoinhibitory checkpoints that maintain the protein in a tightly controlled resting state. GoF mutations disrupt these regulatory constraints, leading to dysregulated SOCE activity that is frequently, but not uniformly, associated with constitutive channel activation depending on the specific mutation and cellular context. While many disease-associated variants localize to the EF hand, a highly conserved helix–loop–helix Ca²⁺ binding motif, and the CC1 (coiled-coil 1) domain involved in molecular regulation of STIM1 activation, an increasing number of mutations in the C-terminal region further expands the mechanistic and clinical spectrum. In this review, we summarize current concepts of molecular STIM1 activation and discuss how distinct mutations perturb specific regulatory elements of the protein. By systematically integrating published case reports into a comprehensive overview, including a mutation–phenotype correlation table, we highlight the remarkable variability in and incomplete penetrance of clinical manifestations. Full article

Tumour necrosis factor-alpha (TNF-α) disrupts bioenergetic homeostasis in skeletal muscle cells through the suppression of ion-dependent ATPase activities, mitochondrial depolarisation, and impairment of antioxidant defences. Carvacrol, a phenolic monoterpenoid constituent of thyme and oregano essential oil, has been shown to exert cytoprotective effects in TNF-α-challenged L6 rat myoblasts. The mechanistic basis of these effects, specifically the relationship between membrane-associated ATPase function, mitochondrial polarisation status, and transcriptional regulation of metabolic stress-response genes, has not been formally characterised. L6 rat myoblasts were exposed to TNF-α (10 ng/mL, 1 h), then treated with carvacrol (6.25 µg/mL, 24 h) in a post-inflammatory rescue paradigm. Cell viability (MTT), membrane integrity (LDH), ion-dependent ATPase activities (Na⁺/K⁺, Ca²⁺, Mg²⁺), antioxidant enzyme activities (catalase, SOD), mitochondrial membrane potential (Muse™ MitoPotential flow cytometry), and SIRT1/AMPK mRNA expression were quantified. TNF-α significantly suppressed Na⁺/K⁺, Ca²⁺, and Mg²⁺-dependent ATPase activities (all p < 0.001), consistent with impaired membrane-associated bioenergetic function. Post-TNF-α carvacrol treatment partially restored all three ATPase activities (p < 0.05) and reduced the proportion of mitochondrially depolarised cells from 31.65 ± 4.25% to 19.0 ± 2.6% (p < 0.05). LDH release, catalase activity, and SOD activity were also significantly modulated. At the transcriptional level, carvacrol increased SIRT1 mRNA by 1.6-fold and AMPK mRNA by 2.0-fold relative to TNF-α-treated cells. An integrative bioenergetic model is proposed in which carvacrol’s membrane-intercalating properties restore the phospholipid environment required for ATPase conformational cycling, attenuating the Ca²⁺ overload that drives mitochondrial permeability transition, and thereby partially preserving Δψm. Transcriptional upregulation of SIRT1 and AMPKα may represent an adaptive response to residual energetic stress. The mechanistic relationships among these endpoints and the causal contribution of SIRT1 and AMPK to observed bioenergetic changes require protein-level and pathway-specific experimental validation. Full article

Muscle wasting contributes substantially to inflammatory bowel disease (IBD)-related disability, but its association with colitis severity across disease stages remains poorly characterized. We therefore assessed skeletal muscle mass, fiber morphology, and voluntary wheel-running performance in Winnie mice—a spontaneous Muc2 mutant model of chronic colitis—in separate female and male homozygous mutant and WT littermate cohorts. Assessments were performed at 5 weeks, before overt colitis, and at 15 weeks, in a cohort with more pronounced colitis. Outcomes included disease activity index (DAI), fecal lipocalin-2 (LCN-2), wheel-running metrics, soleus and tibialis anterior mass, and minimal Feret’s diameter distributions. At 5 weeks, Winnie mice showed no overt disease activity and no consistent structural muscle deficit. In contrast, the 15-week cohort exhibited marked colitis in both sexes, with increased DAI and LCN-2, reduced voluntary wheel-running performance, lower soleus and tibialis anterior mass, and smaller muscle fiber diameters with left-shifted size distributions. Correlation analyses identified associations between fecal LCN-2, skeletal muscle mass and size, and wheel-running distance and velocity, supporting a link between intestinal inflammation and muscle impairment in this model. These cross-sectional data are consistent with reduced voluntary activity and structural myopathy during progression of spontaneous colitis. The Winnie mouse model therefore provides a clinically relevant preclinical platform to study IBD-associated muscle wasting and its association with intestinal inflammation. Full article

Objectives: The genetic architecture of B-cell lymphomas is not fully characterized. We aimed to identify novel candidate variants associated with four common B-cell lymphoma subtypes—diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and marginal zone lymphoma (MZL)—through cross-trait analyses with correlated idiopathic inflammatory myopathies subtypes, dermatomyositis (DM) and polymyositis (PM). Methods: Leveraging shared genetic susceptibility with DM and PM, we applied a pleiotropy-informed conditional false discovery rate (condFDR) method to recompute nominal single nucleotide polymorphism association p-values for each B-cell lymphoma subtype. Associations were considered significant at condFDR <0.01. Functional annotation was performed using FUMA (Functional Mapping and Annotation of Genome-Wide Association Studies), followed by Gene Ontology (GO) enrichment analysis via clusterProfiler, with similar GO terms clustered for interpretation and visualization. Results: We identified 4, 2, 13, and 6 novel candidate loci for DLBCL, FL, CLL, and MZL, respectively. Most loci exhibited regulatory effects on genes involved in adaptive immune responses and cell death pathways. Notably, for DLBCL locus 1q23.3 affects SLAMF genes implicated in natural killer and lymphocyte activation. A trans-eQTL at 2q13 for FL was associated with BCL11A, a multifunctional oncogene. For CLL, a novel locus at 16q24.1 regulates IRF8, a known CLL risk gene. Functional mapping of previously reported CLL risk loci revealed RIPK1 (6p25.2), linked to necroptosis. No enriched biological pathways were detected for MZL risk-associated genes. Conclusions: These findings advance our understanding of the genetic architecture of four B-cell lymphoma subtypes and aim to inform future genetic and functional studies. Full article

Background/Objectives: Idiopathic inflammatory myopathies (IIMs) are chronic immune-mediated disorders, causing striated muscle weakness and extramuscular symptoms. Real-world, single-centre data are needed to interpret phenotype patterns and evolving therapies. Methods: A single-centre, retrospective cohort study was conducted at the Rheumatology Clinic of the National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland from 1 January 2022 to 31 December 2025. Data included demographics, IIM subtypes, extramuscular involvement, co-existing Sjögren disease (SD), biopsy results, autoantibodies, and treatment. Due to sample size, descriptive analysis was used. Results: The study included 35 patients (31.4% men). Mean age was 50.7 years; mean body mass index (BMI) was 26.0 kg/m². The cohort consisted of 10 dermatomyositis (DM), one polymyositis (PM), two immune-mediated necrotising myopathy (IMNM), one inclusion body myositis (IBM), 16 anti-synthetase syndrome (ASyS), four juvenile dermatomyositis (JDM), and one clinically amyopathic dermatomyositis (CADM). SD co-occurred in eight cases, including six cases of ASyS. Anti-Jo1 was observed in 13 ASyS cases and one DM. Glucocorticoids (GCSs) were administered in all patients for induction in addition to cyclophosphamide (28.6%), mycophenolate mofetil (MMF) (51.4%), and methotrexate (MTX) (17.1%). Maintenance therapy included MTX (20%), MMF (31.4%), rituximab (34.3%), azathioprine (AZA) (42.9%), and others. Two DM, two JDM, and one ASyS patient received JAK inhibitors, one DM and one JDM anifrolumab, one IBM sirolimus, and four patients with interstitial lung disease (ILD) nintedanib. Conclusions: This Polish single-centre cohort shows effective use of novel therapies for IIM. Sirolimus, JAK inhibitors, and nintedanib were effective. Co-occurrence of SD in ASyS patients requires further research. Full article

Intensive care unit-acquired weakness (ICUAW) is a common and devastating complication in critically ill patients admitted to the intensive care unit (ICU). ICUAW is characterized by profound skeletal and respiratory muscle weakness and degeneration, as well as peripheral nerve dysfunction. The condition is further categorized into three primary diagnoses: critical illness myopathy (CIM), which affects skeletal muscles, critical illness polyneuropathy (CIP), which affects peripheral nerves, and critical illness polyneuromyopathy (CIPNM), which exhibits features of both CIM and CIP. Although the pathophysiology of ICUAW remains poorly understood, several risk factors have been identified, including female sex, advanced age, prolonged mechanical ventilation, extended ICU stay, prolonged immobilization, multiorgan failure, shock, infection, and other factors related to critical illness and its treatment. Currently, ICUAW is diagnosed after the onset of critical illness, and only once all other possible causes of generalized weakness have been excluded. The most commonly used assessments for suspected ICUAW are the Medical Research Council sum score (MRC-SS) and handgrip dynamometry. However, these tools require active patient participation and are, therefore, impractical for many ICU patients. Non-volitional testing methods, including electromyography (EMG) and nerve conduction studies, can be used to evaluate ICUAW, but these tests are invasive and require specialized training and resources. Due to the lack of effective diagnostic tools and an incomplete understanding of disease mechanisms, management of ICUAW is largely restricted to physical rehabilitation. ICUAW is associated with high morbidity and mortality, and survivors often experience long-term disability and reduced quality of life following hospital discharge. Future areas of research, including biomarker analysis and risk prediction modeling, may enable earlier diagnosis and intervention in critically ill patients. This review summarizes potential diagnostic tools, current management strategies, and short- and long-term prognosis and identifies emerging areas of research aimed at improving outcomes for critically ill patients with suspected ICUAW. Full article

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies are critical biomarkers in myositis, associated with distinct clinical features and prognosis. This study aimed to evaluate the proportion of anti-MDA5 positivity and compare the diagnostic performance of local immunoblotting (IB) with gold-standard immunoprecipitation (IP). We performed a retrospective analysis of 3272 physician-requested anti-MDA5 IB determinations over a five-year period (2019–2023). A subsequent exploratory pilot study of ten Hungarian patients with myositis was conducted to compare IB results with radiolabeled protein IP. Confirmatory in-house enzyme-linked immunosorbent assay (ELISA) was used to distinguish between 140 kDa bands (anti-MDA5 vs. anti-NXP2). Indirect immunofluorescence (IIF) on HEp-2 cells was also evaluated. In the retrospective cohort, 3.7% (n = 121) of samples were non-negative. Among 64 borderline patients, only one (1.6%) had a definitive diagnosis of dermatomyositis (DM). Conversely, the proportion of confirmed myositis cases was notably higher among patients with strong positive IB results. In our exploratory cross-sectional pilot study, complete concordance between the two assays was observed for negative and strong positive results. Discrepancies were noted in borderline and weak positivity ranges, where anti-MDA5 was not detected by IP; instead, alternative autoantibodies were identified. The three IP-confirmed MDA5 positive samples were all validated by ELISA. The characteristic IIF cytoplasmic staining was identifiable in 2 out of 10 cases (20%). In our cohort, borderline IB cases were frequently potential false positives, highlighting the need for careful clinical evaluation. Borderline and weak results require clinical correlation or confirmatory testing to avoid misdiagnosis. Full article

Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues. Full article

White Striping (WS) is a macroscopic defect of the pectoralis major muscle, characterized by distinct white striations that impair meat acceptability and commercial value. It is a phenotype with polygenic inheritance, controlled by several QTLs and genes associated with muscle repair and metabolism. Beyond genetic factors, phenotypic manifestation is strongly modulated by the environment. This review integrates research on genetic predispositions and modulating factors to provide a holistic overview of WS in broilers. The defect predominantly affects heavier birds with high breast yield and elevated ultimate breast pH. LRSAM1 gene, on chromosome GGA17, is identified as a putative candidate gene as its expression co-localizes with the phenotypic QTL. Chromosome GGA5 has recently been identified as the primary genomic region of interest hosting a cluster of specific markers. Research on dietary strategies has extensively explored the manipulation of feed formulations, especially of amino acids. While results for some nutrients like methionine remain conflicting, restricting lysine during the growth phase could be an effective dietary intervention for reducing WS severity. Management offers the most practical short-term solutions, whereas selective breeding enables meaningful and permanent progress across generations, given the moderate heritability of many quality-related traits. Effective mitigation requires an integrated approach combining welfare, environmental control, and precision feeding throughout the production cycle, while acknowledging trade-offs with productivity. To meet evolving consumer expectations, the industry must embrace practices that are simultaneously scientifically rigorous, ethically responsible, and environmentally sustainable. Full article

Background/Objectives: Titin (TTN; OMIM 188840) is the largest known human sarcomeric protein, and pathogenic variants in the TTN gene cause a broad spectrum of inherited myopathies and cardiomyopathies. The extent to which TTN variants may also involve the peripheral nervous system remains poorly defined. We aimed to describe two pediatric patients carrying heterozygous truncating TTN variants with neurophysiological evidence of peripheral nerve involvement, and to review the existing literature on this underrecognized association. Pathogenic variants in the TTN gene are associated with a wide spectrum of inherited myopathies and cardiomyopathies. To date, peripheral neur opathy has not been recognized as a defining feature of TTN-related disorders, and neurophysiological investigations in affected individuals typically demonstrate normal or myopathic findings without evidence of a primary neuropathic process. Here, we report two pediatric patients with heterozygous truncating TTN variants and neurophysiological evidence of bilateral axonal involvement of the deep peroneal nerve. Methods: This case report was structured and reported according to the CARE guidelines. Genetic testing was performed using whole-exome sequencing (Blueprint Genetics Whole Exome Family Test). Nerve conduction studies and needle electromyography were performed using the Galileo NT system. Variant classification followed current ACMG guidelines. Results: The first patient, a 10-year-old girl, presented with a symptomatic distal motor phenotype characterized by bilateral pes cavus, anterior compartment muscle atrophy, areflexia, and steppage gait with onset in early childhood. The second patient, an 8-year-old boy, had subclinical bilateral axonal neuropathy identified during neurophysiological evaluation prompted by intermittent lower limb pain; his father, carrying the same variant, showed concordant neurophysiological abnormalities. In both cases, nerve conduction studies demonstrated reduced compound muscle action potential amplitudes with preserved conduction velocities and distal latencies, consistent with axonal neuropathy. Whole-exome sequencing excluded other established genetic causes of inherited neuropathy in both probands. Conclusions: Although a causal relationship cannot be established, these observations raise the possibility that peripheral nerve involvement may represent an underrecognized feature of the titinopathy spectrum. Prospective studies in larger cohorts of TTN variant carriers are needed to clarify the prevalence and pathophysiological basis of neuropathy in this context. Full article

Pediatric-onset neuromuscular diseases (NMDs) represent a clinically and genetically heterogeneous group of rare disorders, often posing significant diagnostic challenges due to overlapping phenotypes. Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has transformed the diagnostic landscape; however, its clinical utility varies across phenotypic subgroups. We conducted a combined retrospective–prospective cohort study that included 100 pediatric patients with suspected neuromuscular disorders evaluated at a tertiary referral center between 2015 and 2025. Patients were stratified into seven clinically defined diagnostic categories prior to genetic testing. NGS-based diagnostics (primarily WES) were performed following initial clinical and targeted evaluations. Diagnostic yield and predictors of a positive genetic result were analyzed using univariate and multivariable statistical approaches. A molecular diagnosis was established in 71% of patients, including 64% with pathogenic/likely pathogenic variants and 7% with clinically consistent variants of uncertain significance. Diagnostic yield varied significantly across disease categories (p < 0.001), reaching near-complete rates in well-defined phenotypes such as congenital myasthenic syndromes, neuropathies, and metabolic myopathies, while markedly lower yield was observed in unclassified cases (38.2%). Multivariable logistic regression identified disease group as the only independent predictor of diagnostic success (B = −0.436, p = 0.001). Frequently implicated genes included DMD, RYR1, and LAMA2, reflecting a predominance of structural and excitation–contraction coupling defects. NGS demonstrates high diagnostic utility in pediatric neuromuscular disorders, particularly when applied in a phenotype-driven framework. Diagnostic performance is strongly influenced by the degree of clinical definition prior to testing, highlighting the continued importance of expert phenotyping in the genomic era. Full article

Idiopathic inflammatory myopathies constitute a group of immune-mediated disorders primarily affecting skeletal muscle, but they may also lead to significant involvement of internal organs. These conditions are highly heterogeneous, encompassing diverse clinical manifestations and multiple underlying pathophysiological mechanisms. A unifying feature across this disease spectrum is an autoimmune response characterized by the production of highly specific autoantibodies, which are detected in the majority of patients. Genetic studies have identified the principal susceptibility background as the 8.1 ancestral haplotype within the HLA region on chromosome 6. However, genetic predisposition extends beyond HLA loci and includes numerous genes encoding key molecules involved in cytokine production, the regulation of immune signaling pathways, and metabolic processes. In this paper, we review the currently identified genetic loci associated with inflammatory myopathies, with particular emphasis on the HLA system, as well as non-HLA genes and newly identified candidates. Full article

Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder within the spectrum of nuclear envelope diseases, classically characterized by early musculo-tendinous contractures, slowly progressive myopathy, and cardiac involvement dominated by conduction disease and arrhythmias, with variable evolution toward cardiomyopathy and heart failure. This narrative review provides a comprehensive and clinically actionable synthesis of cardiovascular manifestations across EDMD genotypes and phenotypes, outlining pragmatic diagnostic and therapeutic pathways for real-world care. A targeted literature search was performed in PubMed, Embase, and Web of Science, focusing on studies addressing cardiovascular involvement in EDMD. Relevant original studies, case series, registries, guideline documents, and high-quality reviews were selected and synthesized narratively, with particular emphasis on diagnostic strategies, risk stratification, and management approaches. Cardiac involvement in EDMD encompasses a broad and heterogeneous spectrum, including atrial disease and conduction disturbances, ventricular arrhythmias, dilated cardiomyopathy, thromboembolic complications, and sudden cardiac death. Phenotypic expression varies according to the underlying genetic substrate, with distinct atrial- and ventricular-dominant trajectories. Early recognition and structured cardiovascular surveillance are essential to guide timely intervention, including anticoagulation, device therapy, and heart failure management. Despite growing awareness, significant gaps remain in risk prediction and standardized management strategies. EDMD represents a paradigmatic model of cardiomyopathy characterized by prominent electrical instability and systemic involvement. A structured, genotype- and phenotype-informed approach centered on early surveillance, proactive arrhythmia and thromboembolic risk management and timely device therapy may improve clinical decision-making in real-world settings. Future perspectives include the integration of precision medicine and the development of gene- and pathway-targeted therapies, with the potential to shift from symptomatic management toward disease-modifying strategies. Full article

Skeletal muscle is vital for movement and metabolism, and its dysfunction underpins disorders like muscular dystrophy and sarcopenia, severely impacting life quality. In these diseases, various cell death pathways are pivotal, driving core pathological features such as fiber loss and chronic inflammation. This study reviews the central role of cell death in skeletal muscle diseases, and analyzes its roles and mechanisms in genetic muscle disorders such as Duchenne muscular dystrophy (DMD), glycogen storage diseases (GSD), mitochondrial myopathies, as well as acquired muscle disorders such as idiopathic inflammatory myopathy, sarcopenia, rhabdomyolysis, and myasthenia gravis (MG). We also explore the potential of cell death-related molecules as biomarkers and discuss emerging therapeutic strategies that target these pathways, aiming to provide new insights for diagnosis and treatment. Full article