Search Results (550)

Muscle regeneration following injury reveals a striking paradox: the same phenomenon, fiber branching, can serve as both a beneficial adaptation in healthy muscle and a pathological hallmark in disease. In healthy muscle, branched fibers emerge as an adaptive response to extreme mechanical loading, redistributing stress, enhancing hypertrophy, and protecting against injury. Conversely, in conditions such as Duchenne Muscular Dystrophy, excessive and complex branching contributes to mechanical weakness, increased susceptibility to damage, and progressive functional decline. This review explores the dichotomy of fiber branching in muscle physiology, synthesizing current research on its molecular and cellular mechanisms. By understanding the paradoxical nature of fiber branching, we aim to uncover new perspectives for therapeutic strategies that balance its adaptive and pathological roles to improve outcomes for muscle diseases. Full article

Background: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the DMD gene, one of the most significant and most mutation-prone genes in the human genome. Although global mutation registries are well developed, genetic data from Central Asian populations remain extremely limited, leaving essential gaps in regional epidemiology and in the understanding of genotype–phenotype patterns. Methods: We conducted a retrospective analysis of patients with genetically confirmed dystrophinopathy in Kazakhstan. Variants were identified using multiplex ligation-dependent probe amplification (MLPA) for exon-level copy number alterations and next-generation sequencing (NGS) with Sanger confirmation for sequence-level changes. All variants were classified under ACMG guidelines. Statistical modelling incorporated mutation-class grouping, exon-hotspot mapping, reading-frame status, CPK stratification, chi-squared association testing, Spearman correlations, Kaplan–Meier ambulation survival curves, and multivariable logistic and Cox regression. Results: multi-exon deletions were the predominant mutation class, with a marked concentration within the canonical hotspot spanning exons 44–55. Recurrent deletions affecting exons 46–50 and 45–50 appeared in several unrelated patients. NGS confirmed severe protein-truncating variants, including p. Lys1049* and p. Ser861Ilefs*7. Phenotypic severity followed a consistent hierarchy: hotspot-associated deletions and early truncating variants showed the earliest loss of ambulation, whereas splice-site variants and duplications demonstrated the mildest courses. CPK levels correlated with the extent of genomic involvement, though extreme elevations did not consistently predict early functional decline. Regression models identified hotspot localization and out-of-frame effect as independent predictors of ambulation loss. Conclusions: This study provides the first statistically modelled characterisation of DMD gene mutations in Kazakhstan. While the mutational landscape largely mirrors global patterns, notable variability in clinical severity suggests the presence of population-specific modifiers. Integrating comprehensive molecular diagnostics with statistical-genetics approaches enhances prognostic accuracy and supports the development of mutation-targeted therapeutic strategies in Central Asia. Full article

Skeletal muscle atrophy underlies sarcopenia, frailty, and muscular dystrophies, but the molecular mechanisms linking oxidative stress to muscle degeneration remain incompletely understood. We previously identified protein complex formation between transient receptor potential canonical 3 (TRPC3) and NADPH oxidase 2 (Nox2) as a key driver of anthracycline-induced myocardial atrophy. Here, we investigated whether this complex also contributes to skeletal muscle wasting. In skeletal muscle from sciatic nerve transection model mice and Duchenne muscular dystrophy (mdx) mice, TRPC3-Nox2 complex formation was enhanced. TRPC3 deletion significantly attenuated denervation-induced soleus atrophy and reduced reactive oxygen species (ROS) production. TRPC3-Nox2 complex formation was upregulated in the soleus muscle (SM) of mdx mice. Pharmacological disruption of the TRPC3-Nox2 interaction improved muscle size and strength and reduced plasma creatine kinase in mdx mice. A recombinant adeno-associated virus (AAV) encoding a TRPC3 C-terminal peptide was used to suppress TRPC3-Nox2 complex formation in vivo. AAV-mediated expression of TRPC3 C-terminal peptide mitigated muscle wasting (CSA) in mdx mice, while muscle strength and plasma CK were not significantly improved. Thus, TRPC3-Nox2 complex formation may be a pivotal driver of oxidative stress-mediated skeletal muscle atrophy. Targeting this protein–protein interaction represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD) and other intractable muscle-wasting disorders. Full article

Background/Objectives: Pediatric osteoporosis is a multifactorial condition characterized by impaired bone mineralization and increased fracture risk, particularly vertebral compression fractures. This study aims to evaluate the diverse etiology, diagnostic challenges, and treatment options for pediatric osteoporosis in a cohort of affected children. Methods: We reviewed eleven pediatric patients (aged 5–16 years) diagnosed with vertebral fractures and osteoporosis, who were hospitalized between 2020 and 2024 at the Department of Endocrinology and Metabolic Diseases at PMMH-RI in Lodz. Clinical evaluation included medical history, physical examination, biochemical markers of bone metabolism, and imaging techniques such as dual-energy X-ray absorptiometry (DXA) to determine underlying causes of bone fragility. Results: The cohort presented a broad etiological spectrum, including seven patients with genetic disorders (e.g., mutations in COL1A1, LRP5, SGMS2, and ALPL genes) and secondary osteoporosis due to chronic diseases requiring prolonged glucocorticoid therapy (two patients with Duchenne muscular dystrophy (DMD), one patient with Crohn’s disease) or endocrinological disorders (one patient with Cushing disease). Vertebral fractures were confirmed in all patients, with back pain as the predominant symptom. Low bone mass (BMD Z-score < −2.0) was observed in eight individuals; in others, clinical signs of skeletal fragility were present despite Z-scores above this threshold. Mild biochemical abnormalities included hypercalciuria (3/11 cases) and vitamin D deficiency (6/11 cases). Height adjustment improved BMD interpretation in short-stature patients. Most children received bisphosphonate therapy, supplemented with calcium and vitamin D. In two patients, bisphosphonates were not used due to lack of parental consent or underlying conditions in which such treatment is not recommended. Conclusions: Pediatric osteoporosis requires a multidisciplinary diagnostic and therapeutic approach, integrating clinical, biochemical, and genetic factors. It is a heterogeneous and often underrecognized condition, with vertebral fractures frequently serving as its earliest sign—even in the absence of overt symptoms or low bone mass. This underscores the need for clinical vigilance, as significant skeletal fragility may occur despite normal BMD values. Importantly, pediatric osteoporosis may also impact the attainment of peak bone mass and ultimately affect final adult height. Early diagnosis through thorough assessment, including height-adjusted DXA, and a multidisciplinary approach are essential to ensure timely management and prevent long-term complications. Full article

Background: Duchenne/Becker muscular dystrophy (DMD/BMD) is associated with a wide spectrum of brain-related comorbidities. Methods: This retrospective study assesses the neuropsychiatric profile of DMD/BMD patients and the hypothesis of a functional-versus-structural approach of dystrophin gene variants/impaired isoforms in relation to brain comorbidities. Patients with documented mutation in the DMD gene and neuropsychiatric assessments were included. Seven comorbidities were analyzed based on variant location and dystrophin brain isoform disruption. The clustering of comorbidities and genotype–phenotype correlations were studied. Results: 264 DMD/BMD patients met inclusion criteria. 22 variants have never been described before. A high prevalence of neuropsychiatric comorbidities was identified in the cohort with higher values in patients with distal mutations. The number of comorbidities increased with the number of brain dystrophin isoforms predicted to be lost. Functional-versus-structural comparison revealed that Dp140 5′UTR variants might not affect protein expression. Epilepsy and intellectual disability (ID) showed significant association in this cohort. Neuropsychiatric phenotype varied greatly in patients with identical variants, even between siblings. Conclusions: This is one of the largest European cohorts for which all these comorbidities were studied in association with DMD gene mutation site and the first study of this kind performed on the Eastern European DMD/BMD population. Our group analyzed, for the first time, Dp140 5′UTR variants in relation to all neuropsychiatric phenotypes and showed that epilepsy and ID are strongly associated in DMD/DMB patients. Full article

Background: Video-based biomechanical running gait analysis is widely used to optimise technique, guide footwear selection, and identify orthopaedic risk factors. Despite the increasing availability of such assessments, it is often assumed—without strong empirical support—that key kinematic parameters of running gait remain stable over short periods of time. This study aimed to examine the short-term stability of key joint angles during running using a standard 2D video-based kinematic analysis. Specifically, it was investigated whether these angles change within the first 4 min of treadmill running under three defined conditions: barefoot at 12 km h⁻¹, shoed at 12 km h⁻¹, and shoed at 14 km h⁻¹, in a homogeneous sample of twelve young, trained, male recreational soccer players. Methods: Participants completed three four-minute runs. Joint angles were quantified manually from 2D video recordings. Temporal variation was analysed using repeated-measures statistics, intraclass correlation coefficients (ICCs), and minimal detectable changes (MDCs). Results: Six out of nine joint angles showed statistically significant temporal changes, mainly in hip extension, knee flexion, the Duchenne angle, the Trendelenburg angle, the leg axis angle, and heel-bottom angle. Lower leg angle and Achilles tendon angle remained stable. ICCs showed moderate to excellent agreement, indicating high within-session consistency across all angles. Discussion: Under the applied study protocol, significant short-term variations were observable in several joint angles during the first four minutes of running. These findings highlight the importance of analysing multiple strides and considering measurement uncertainty when interpreting short-duration running kinematics. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked hereditary disorder caused by pathogenic variants in the DMD gene encoding the dystrophin protein. The absence of functional dystrophin leads to destabilization of the dystrophin-associated glycoprotein complex (DAPC), sarcolemmal damage, and progressive degeneration of muscle fibers. Current therapeutic strategies focus on restoring dystrophin expression using genome editing approaches. Adeno-associated virus (AAV) vectors represent the primary delivery platform due to their strong tropism for muscle tissue, low immunogenicity, and ability to achieve long-term transgene expression. However, the limited packaging capacity of AAV (~4.7 kb) necessitates the use of truncated mini- and micro-dystrophin transgenes as well as compact genome editing systems (SaCas9, NmeCas9, Cas12f, TIGR-Tas, and others). Major challenges include immune responses against the viral capsid and transgene products, as well as the inability to perform repeated administrations. Moreover, the duration of expression is limited by the episomal nature of AAV genomes and their loss during muscle fiber regeneration. Despite substantial progress, unresolved issues concerning safety, immunogenicity, and stability of genetic correction remain, defining the key directions for future research in DMD therapy. Full article

This research aims to identify a suitable design solution that models the behavior of a human’s center of mass. This solution can be implemented in an exoskeleton structure that is especially designed for children who require walking assistance and rehabilitation. The primary problem posed by exoskeleton designs is representing the effect of ground–foot contact on exoskeleton behavior under kinematic and dynamic conditions. To mitigate this, our main research objective was to develop a mechanical system that demonstrates the human center of mass (CoM) behavior on an exoskeleton designed for children with Duchenne Muscular Dystrophy. The research focuses on modeling human CoM behavior under kinematic circumstances and transferring this into a mechanical system conceptual design. The obtained results validate the proposed mechanical system through a comparative analysis between numerical processing, virtual prototyping, and experimental specific methods and procedures. Full article

Background/Objectives: The article presents data on Duchenne muscular dystrophy (DMD) in the Republic of North Ossetia-Alania (RNOA), describing the population characteristics of the disease among children in RNOA (2006–2023). Methods: The number of newborns was 172,115, with 86,057 boys from 2006 to 2023. During the reporting period, 19 families (23 patients, including 22 boys) were identified. The molecular and genetic characteristics of the patients were analyzed throughout the entire observation period, which began in 1998. Results: The prevalence of the disease was 1:3912 among newborn boys (95%CI: 1:2584–1:6242), which is slightly higher than in other regions of the Russian Federation (RF) and most countries around the world. The spectrum of DMD genetic variants in RNOA aligns with worldwide patterns but reveals differences in frequencies compared to RF data. The frequency of exon deletions in the DMD gene range from 65.0 to 70.0% (60% in RNOA vs. <50% in RF) worldwide, for duplications—9.0–11.0% globally (16% in RNOA), and for nonsense variants—9.7–26.5% worldwide (20% in RNOA). Twelve patients (41.0%) in RNOA qualified for therapy, and Translarna was prescribed in most cases. In the cohort of children, one girl was identified with classic DMD, confirmed by genetic studies. Different limitations of the study were hindered by the small cohort size, patients’ remote residences, and poor therapy compliance of our patients. Conclusions: The heterogeneity of mutation spectrum across different populations underscores the influence of ethnic background. Consequently, this study highlights the importance of population-specific studies for improving DMD care. Full article

Augmentative and alternative communication (AAC) enables digital access for individuals with severe motor impairment. Conventional contact-based switches rely on residual voluntary movement, limiting efficiency. We report the clinical application of a novel, researcher-developed noncontact assistive switch, the Augmentative Alternative Gesture Interface (AAGI), in a 39-year-old male with late-stage Duchenne Muscular Dystrophy (DMD) retaining minimal motion. The AAGI converts subtle, noncontact gestures into digital inputs, enabling efficient computer operations. Before intervention, the participant used a conventional mechanical switch, achieving 12 characters per minute (CPM) in a 2 min text entry task and was unable to perform high-speed ICT tasks such as gaming or video editing. After 3 months of AAGI use, the input speed increased to 30 CPM (+2.5-fold), and previously inaccessible tasks became feasible. The System Usability Scale (SUS) improved from 82.5 to 90.0, indicating enhanced usability, whereas the Short Form 36 (SF-36) Social Functioning (+13) and Mental Health (+4) demonstrated meaningful gains. Daily living activities remained stable. This case demonstrates that the AAGI system, developed by our group can substantially enhance communication efficiency, usability, and social engagement in advanced DMD, highlighting its potential as a practical, patient-centered AAC solution that extends digital accessibility to individuals with severe motor disabilities. Full article

Duchenne muscular dystrophy (DMD), which results from mutations that disrupt the expression of dystrophin proteins, is characterized by progressive muscle fiber wasting and the development of skeletal muscle fibrosis. The severe pathology leads to loss of ambulation, respiratory insufficiency, cardiomyopathy, and early death in patients. Dystrophin-focused therapies based on adeno-associated viral (AAV) vector-mediated gene addition, antisense oligonucleotide-induced repair of the transcript reading frame, and chemically driven stop codon readthrough have been conditionally approved for use in subsets of patients. From trials, it is apparent that these therapies act to stabilize the disease phenotype rather than improve it significantly, meaning that early treatment results in better outcomes. AAV-mediated delivery of a form of utrophin, a structural and functional homolog of dystrophin, GALGT2, a sarcolemmal stabilizer, and Klotho, the anti-aging hormone that is silenced in a mouse model of DMD as a result of the disease pathology, have been explored in preclinical compensatory gene addition studies. Recombinant follistatin protein has been used to target the fibrosis seen. An all-in-one type of therapy is likely to provide a synergistic effect such that efficacy of the dystrophin restoration strategy would be improved. For this, CRISPRa could hold potential through the targeting of multiple relevant genes simultaneously. The suitability of targeting these genes will be discussed, as will the stages of the development of CRISPRa for DMD. A perspective on the future prospects of CRISPRa in relation to likely issues that would need addressing and how they may be overcame will be given. Full article

Background: The COVID-19 pandemic disrupted healthcare systems, disproportionately affecting individuals with rare diseases. This study explores the health-related quality of life and financial burden in the post-pandemic context among children with Duchenne Muscular Dystrophy and their families in Greece, providing insights into health system performance. Methods: A multicenter, cross-sectional study was conducted in two neuromuscular clinics in Greece. Fifty families (response rate 67%) completed standardized quality of life instruments (PedsQL™ 4.0 Generic Core Scale; PedsQL™ 3.0 DMD Module) and a socioeconomic questionnaire. Descriptive and correlation analyses assessed associations between functional status, financial strain, and psychosocial indicators. Results: Children with Duchenne Muscular Dystrophy reported moderate-to-severe reductions in physical and emotional well-being, and substantial out-of-pocket expenditures. Families with greater financial strain or wheelchair-dependent children had significantly lower health-related quality of life scores. Insurance coverage was positively associated with emotional and psychosocial functioning. Conclusions: Greek families living with Duchenne Muscular Dystrophy continue to face significant financial and psychosocial challenges in the post-pandemic period. While the cross-sectional design does not allow causal attribute to COVID-19 pandemic, the results underscore the need to strengthen financial protection, coordinated multidisciplinary care, and equitable access to support services for rare disease management. Full article

Background/Objectives: The progressive life-limiting disorder Duchenne muscular dystrophy (DMD) arises from the absence of dystrophin protein at the muscle cell membrane, which leads to progressive contraction-induced damage. Despite the advancements in molecular therapies aimed at reintroducing (partially functional) dystrophin in patients, a cure for DMD remains elusive. Taurine supplements have been proposed as a potential supportive treatment for DMD, based upon encouraging results in the mouse model mdx. Methods: In a previous study, we observed improvements in skeletal muscle histology and a reduction in the expression of inflammatory markers after short-term treatment with 4.6 g taurine per kg body weight during the initial stages of the disease. In this follow-up study, we examined cell death and tissue restoration protein levels in mdx subjected to the same treatment regimen, utilizing proteome arrays, Western blotting, and immunofluorescence. Results: We report that, while the levels of apoptotic and autophagic proteins remained constant, selective and significant decrease in receptor-interacting Serine/Threonine protein kinase 1 (RIP1) levels could be observed in taurine-treated mdx compared to untreated mdx. RIP1 was immunolocalized to muscle fibers, with faint homogeneous staining in age-matched healthy controls shifting to a heterogeneous staining pattern in mdx, the latter diminishing with taurine treatment. Conclusions: Given its role as a molecular switch in cell fate decisions, the observed taurine-induced downregulation of RIP1 supports the potential beneficial effects of the osmolyte in mdx. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal and cardiac muscle degeneration driven by inflammation and fibrosis, ultimately leading to cardiomyopathy and premature death. Deramiocel, an allogeneic cell therapy composed of cardiosphere-derived cells (CDCs), has demonstrated potent anti-fibrotic and immunomodulatory effects in preclinical models and clinical trials, including HOPE-2 and its open-label extension (HOPE-2 OLE), where Deramiocel treatment significantly attenuated progression of skeletal and cardiac muscle dysfunction. Methods: CDCs in Deramiocel were cultured to generate CM enriched with secreted exosomes and factors, which was subsequently applied to primary human dermal fibroblasts (HDFs). Following co-culture, ex-pression of collagen type I alpha 1 (COL1A) and collagen type III alpha 1 (COL3A) was measured by qRT-PCR. Non-conditioned media serves as a control in the assay. Reduction in COL1A and COL3A expression therefore provides a direct and clinically relevant measure of the anti-fibrotic activity of Deramiocel. Results: A novel in vitro potency assay was developed to quantify the anti-fibrotic activity of Deramiocel. Conditioned media (CM) from over one hundred Deramiocel manufacturing lots significantly suppressed expression of collagen type I alpha 1 (COL1A) and collagen type III alpha 1 (COL3A) in primary human dermal fibroblasts compared with non-conditioned media controls, establishing a robust, reproducible readout of anti-fibrotic activity. The effect was dose-dependent and abrogated by sequential depletion of exosomes and soluble proteins, implicating both as critical mediators of Deramiocel’s mechanism of action. Importantly, CDCs in Deramiocel lots classified as potent by this assay were shown to exert a clinically meaningful benefit in DMD patients in the HOPE-2 and HOPE-2 OLE studies. Conclusions: This assay represents a mechanistically informative, therapeutically relevant, reproducible, scalable, and regulatory-compliant approach for assessing Deramiocel potency, enabling consistent manufacturing, and facilitating the continued development of Deramiocel as a disease-modifying therapy for DMD. Full article

Proteomics of dystrophic muscle samples is limited by the amount of protein that can be extracted from patient biopsies. Cells and tissues derived from patient-derived induced pluripotent stem cells (iPSCs) can be an expandable alternative source. We have patterned iPSCs from three Duchenne muscular dystrophy (DMD) patient lines into skeletal muscle cells using a two-dimensional as well as our three-dimensional organoid differentiation system. Probes with sufficient protein amounts could be extracted and prepared for mass spectrometry. In total, 3007 proteins in 2D and 2709 proteins in 3D were detected in DMD patient probes. A total of 83 proteins in 2D and 338 proteins in 3D can be described as differentially expressed between DMD and control patient probes in a post hoc test. We have identified and we propose Myosin-9, Collagen 18A, Tropomyosin 1, BASP1, RUVBL1, and NCAM1 as proteins specifically altered in their expression in DMD for further investigation. Proteomics of skeletal muscle organoids resulted in greater consistency of results between cell lines in comparison to the two-dimensional myogenic differentiation protocol. Full article