Search Results (1,023)

The dystrophin–glycoprotein complex (DGC) is a structural and signaling network of cardiac muscle. It connects the extracellular matrix to the intracellular cytoskeleton. Dystroglycan, a component of the DGC, plays an essential role in maintaining the integrity of the sarcolemma of cardiac muscle. It contributes to sarcolemma stability, force transmission, mechanotransduction, calcium homeostasis, and cardiomyocyte survival. While the role of dystroglycan signaling is well established in many inherited disorders such as Duchenne muscular dystrophy, it is less studied in acquired heart failure with reduced ejection fraction (HFrEF). Emerging evidence suggests that dystroglycan remodeling may also occur in HFrEF. This review critically analyzes dystroglycan signaling in healthy and failing hearts, with particular emphasis on its emerging role in acquired HFrEF, including cardiac remodeling and fibrosis. Full article

Duchenne and Becker X-linked muscular dystrophies are no longer viewed as disorders arising solely from passive sarcolemmal fragility but as diseases that progress because of disruption of cellular mechanotransduction. Evidence is accumulating that the gating of TRPC1 and TRPC3 mechanosensitive channels is altered in the absence of dystrophin, resulting in a breakdown of sarcoplasmic calcium homeostasis and preferential loss of type II glycolytic muscle fibres, while type I oxidative fibres are spared. TRPC1-mediated Ca²⁺ influx is known to activate the calcineurin–NFAT pathway, upregulating PGC-1α transcriptional activity to promote mitochondriogenesis, antioxidant defences, and the oxidative muscle phenotype. Calcineurin signalling also activates a compensatory pathway in dystrophinless muscle by inducing the expression of utrophin, a dystrophin autosomal homologue, capable of substituting for dystrophin at the muscle surface. This perspective explores the possibility that non-mechanical biophysical stimuli can be used to restore calcineurin signalling by non-invasively activating TRPC1. Pulsed electromagnetic field (PEMF) exposure has been shown to stimulate TRPC1-mediated Ca²⁺ entry and calcineurin-dependent signalling in skeletal muscle and may serve as a gentle method to induce utrophin expression in X-linked muscular dystrophies. By activating calcineurin compensatory mechanisms in these disorders, PEMF-based paradigms warrant future investigation as mechanistically grounded adjuvants to conventional therapies. Full article

Background: Duchenne muscular dystrophy (DMD) is a monogenic disorder caused by dystrophin deficiency, but its downstream molecular consequences involve complex and interconnected regulatory networks. Methods: In this study, we performed a cross-species integrative transcriptomic analysis of skeletal muscle RNA-seq datasets from humans, mice, and rats to identify conserved molecular signatures of DMD. Results: Differential expression analysis identified 1367 shared differentially expressed genes (DEGs) across the three datasets, of which 62 showed concordant directionality in all species. After ortholog filtering, which excluded five genes lacking confirmed one-to-one orthologs across all three species, 57 conserved genes were retained as the conserved DMD-associated gene (DAG) set. Functional enrichment (GO/KEGG) was performed on the cross-species shared DEG set, and the 57 conserved genes were subsequently mapped onto these enrichment outputs. The DAG-containing categories included focal adhesion, apoptosis, and calcium signaling, which remained significant after Benjamini–Hochberg correction, together with nominally enriched Rap1 signaling. Integration of circRNA, miRNA, and mRNA data further identified a candidate, computationally inferred hub-dominated ceRNA network involving DMD, RYR3, KLF4, ID1, TIMP4, and CASP7. Conclusions: Together, these findings support a model in which conserved core molecular programs are superimposed on species- and context-dependent transcriptional responses, prioritizing the conserved genes and candidate circRNA-related network components for future mechanistic and translational studies. Full article

Primary dystrophin deficiency, caused by X-chromosome mutations within the DMD gene, encompasses a continuous clinical spectrum of neurological, muscular, and cardiac disorders known as dystrophinopathies that exhibit profound phenotypic variability driven by specific mutation profiles and epigenetic factors. This comprehensive review analyzes the clinical and molecular characteristics of seven primary classifications: Duchenne muscular dystrophy (DMD), a severe childhood myopathy caused by a complete absence of the protein that leads to loss of ambulation and fatal cardiorespiratory failure in youth; Becker muscular dystrophy (BMD), a milder variant with partial protein deficiency that preserves walking capabilities into adulthood and prolongs life expectancy; pseudometabolic dystrophinopathic syndrome, featuring exercise intolerance, cramps, and recurrent rhabdomyolysis that mimics metabolic diseases; asymptomatic dystrophinopathy, representing the mild end of the spectrum identified incidentally through chronically elevated creatine kinase levels; brain dystrophin-related syndrome, where the disruption of distal isoforms like Dp140 and Dp71 results in neurodevelopmental and neuropsychiatric comorbidities such as ADHD, autism, and intellectual disability; X-linked dilated cardiomyopathy (XLDCM), a cardiac-selective condition causing severe heart failure and arrhythmias while sparing skeletal muscle function; and female dystrophin-related syndrome, distinguishing between familial carriers—who can manifest symptoms due to skewed X-chromosome inactivation—and rare sporadic females who develop an exceptional, severe, Duchenne-like phenotype due to cytogenetic accidents such as Turner syndrome or chromosomal translocations. Ultimately, advancements in molecular testing (NGS and WGS) have significantly optimized diagnostic precision, proving essential for implementing early cardioprotective care, accurate genetic counseling, and the development of future tissue-specific targeted gene therapies. The present study also discusses the psychosocial impact that the disease has on patients. Full article

Background: Beckers muscular dystrophy (BMD) is a clinically heterogeneous dystrophinopathy caused by in-frame mutations in the dystrophin gene, resulting in variable disease severity. This variability limits the effectiveness of standardized functional measures for tracking progression. Circulating biomarkers, including urinary titin fragments generated during muscle injury, offer a promising non-invasive approach for assessing disease status. Methods: Mass spectrometry-based urinary proteomic profiling identified titin fragments as candidate biomarkers of muscle injury in BMD. These titin fragments were validated by two independent methods, targeted mass spectrometry and ELISA, using subsets of ambulatory BMD, non-ambulatory BMD and age matched healthy volunteers. Results: Urinary titin levels were significantly elevated by 4.56-fold and 2.32-fold in ambulatory and non-ambulatory BMD patients, respectively, compared with healthy controls. Titin levels also distinguished ambulatory from non-ambulatory BMD patients, demonstrating potential utility for monitoring disease progression and therapeutic response. Conclusions: Urinary titin fragments represent a promising non-invasive biomarker for BMD, with potential applicability to related neuromuscular disorders and clinical trials evaluating disease progression and treatment efficacy. Full article

Myostatin (GDF8) is a member of the transforming growth factor-β (TGF-β) superfamily. Myostatin gene mutations or inhibition of the Myostatin/Activin pathway results in increased skeletal muscle mass, demonstrating its role as a negative regulator of skeletal muscle. Myostatin blockade is a promising strategy for increasing muscle mass in myopathies such as Duchenne Muscular Dystrophy (DMD); however, it faces considerable challenges in clinical translation, in part due to the progressive nature of the disease. Here we tested the ability of JA16 monoclonal antibody-mediated myostatin blockade to improve the dystrophic phenotype in newborn mdx mice (an animal model of DMD). Myostatin inhibition led to significant increases in muscle size, fiber number and cross-sectional area along with increased absolute force alongside reduced post-eccentric contraction force drop and reduced serum creatine kinase. We used the Multiparametric Muscle Improvement Score (MMIS) to objectively quantitate benefits in this preclinical study and determined that the magnitude of improvements exceeded those reported using the exact same intervention in older mdx mice treated for the same duration. This study demonstrates an age-dependent aspect of this intervention and suggests that earlier interventions may provide greater therapeutic benefits. Full article

Fragile X syndrome (FRAX) is caused by CGG repeat expansion in the FMR1 gene, which triggers aberrant DNA hypermethylation, chromatin condensation, and transcriptional gene silencing. However, the mechanism that underlies this repeat-induced epigenetic defect remains poorly understood. SMCHD1 is a chromatin regulator that promotes de novo DNA methylation and heterochromatin formation at long repetitive elements, including the D4Z4 macrosatellite repeat implicated in facioscapulohumeral muscular dystrophy (FSHD). Given the mechanistic parallels between FSHD and FRAX, we hypothesized that SMCHD1 contributes to repeat-induced FMR1 hypermethylation. To test this, we disrupted SMCHD1 in an XY FRAX human embryonic stem cell (hESC) line carrying a heavily methylated CGG-expanded FMR1 allele. Despite efficient loss of SMCHD1, FMR1 hypermethylation remained unchanged, indicating that SMCHD1 is dispensable for FMR1 gene silencing. We next combined SMCHD1 knockout with CRISPR-mediated CGG repeat contraction to determine whether removal of the pathogenic mutation could restore the aberrant methylation. Nevertheless, FMR1 hypermethylation was preserved in all edited clones. These findings demonstrate that, unlike D4Z4 silencing in FSHD, FMR1 repeat-induced hypermethylation does not depend on SMCHD1 activity. Moreover, correction of the underlying CGG expansion through repeat contraction is insufficient to restore the normal hypomethylated state of the FMR1 locus in pluripotent stem cells. Full article

Background: Pathogenic variants in the DMD gene are a frequently overlooked cause of dilated cardiomyopathy (DCM) in idiopathic cases, especially when skeletal myopathy is mild or seemingly absent. Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy are at opposite ends of this clinical spectrum but result from pathogenic variants in the same gene. Cardiomyopathy is a major cause of premature death in muscular dystrophies. Case presentation: We describe a 37-year-old man who underwent orthotopic heart transplantation for presumed idiopathic DCM with refractory heart failure. He had a six-year history of progressive proximal weakness, pseudohypertrophy of the calf, a positive Gowers sign, and markedly elevated creatine kinase (6638 IU/L). Multiplex ligation-dependent probe amplification (MLPA) revealed an in-frame deletion of exons 45–47 of DMD [c. (6438+1_6439-1)_(6912+1_6913-1) del; NM_004006.2], confirming BMD. Immunofluorescence showed reduced and patchy dystrophin expression. Conclusions: To our knowledge, this is the first documented heart transplant in a patient with BMD in Mexico. This case demonstrates the value of considering muscular dystrophy in the differential diagnosis of apparently idiopathic dilated cardiomyopathy (DCM), a step that opens the door to accurate diagnosis, carrier screening, and genetic counseling, and supports the view that heart transplantation is a viable option in carefully selected patients with muscular dystrophy cardiomyopathy. Full article

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that abolish dystrophin expression. Prime editing enables precise genome modification without generating double-strand DNA breaks or requiring donor DNA templates. We established an in vitro prime editing workflow to generate and subsequently correct the mdx5cv mutation in mouse C2C12 myoblasts. Following optimization of engineered prime editing guide RNAs (epegRNAs) and PAM-flexible prime editors, wild-type cells were edited, clonally isolated, and genotyped. Mutation correction was then evaluated using optimized epegRNA designs. Two rounds of prime editing introduced the mdx5cv mutation into approximately 20% of alleles in C2C12 cells creating the mdx5cv C2C12 cell line. Clonal isolation yielded five homozygous mutant clones among 59 expanded colonies. Optimization studies identified an epegRNA containing a 16 nucleotide reverse transcription template and a 10 nucleotide primer binding site (RTT16/PBS10) as the most efficient design. Correction of the pathogenic allele reached approximately 26%, whereas longer PBS lengths reduced editing efficiency. In silico off-target analysis using Cas-OFFinder identified no candidate genomic loci with fewer than three mismatches for the spacer sequences used in either mutation generation or correction, suggesting a favorable predicted specificity profile. Corrected mdx5cv C2C12 myoblasts retained their capacity to differentiate into multinucleated myotubes. Representative Western blot analysis detected dystrophin protein expression in differentiated corrected mdx5cv myotubes, consistent with successful correction of the pathogenic mutation. These findings establish a robust prime editing platform for both the generation and correction of the mdx5cv mutation and provide proof of concept that precise correction of the pathogenic mutation is associated with restoration of dystrophin expression following myogenic differentiation. Full article

Collagen VI-related myopathies (COL6-RM) are rare hereditary disorders characterized by skeletal muscle dysfunction and skin manifestations, including keratosis pilaris, hypertrophic scars, and keloids. We recently found that alopecia is a novel and previously unrecognized scalp phenotype in COL6-RM; however, the precise pathogenetic mechanisms underlying hair follicle dysfunction in these patients remain incompletely understood. We performed a comprehensive immunohistochemical, ultrastructural, and proteomic characterization of scalp biopsies from six COL6-RM patients presenting with hair loss and scalp itching. We found structural alterations in the hair follicle extracellular matrix architecture, particularly in the inner fibrous sheath surrounding the hair follicle. In addition, the analysis of the perifollicular adipose tissue and derived cell cultures showed changes in lipid droplet size consistent with a tendency toward cell hypertrophy. Strikingly, proteomic profiling of adipokines revealed a pro-inflammatory and extracellular matrix-remodeling signature. Consistent with inflammation and extracellular matrix remodeling, CD68 macrophages and MMP2 expression were increased in the dermis of COL6-RM patients, particularly around the perifollicular adipocytes. Overall, these data indicate a complex pathological signature involving ECM and adipose tissue remodeling. In this context, collagen VI emerges as a potential regulator of the hair follicle microenvironment. Full article

Background: Neurodevelopmental disorders, including Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and Specific Learning Disorder (SLD), as well as neuromuscular conditions such as Duchenne Muscular Dystrophy (DMD), are frequently associated with emotional and behavioral difficulties that may affect children’s functioning and family well-being. However, direct comparisons across these heterogeneous clinical populations remain limited. This study aimed to compare emotional and behavioral profiles across children and adolescents with ASD, ADHD, SLD, and DMD using the Child Behavior Checklist (CBCL/6–18). Methods: This cross-sectional comparative study included 197 children and adolescents (ASD: 47; SLD: 50; ADHD: 50; DMD: 50) assessed at the Clinical Psychology Unit of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome, Italy) between 2017 and 2024. Emotional and behavioral functioning was evaluated using the parent-report CBCL/6–18. Group differences were examined using one-way ANOVA or Welch’s ANOVA, as appropriate, followed by Tukey’s HSD or Games–Howell post hoc comparisons. Results: Significant group differences emerged for Internalizing Problems, Externalizing Problems, and Total Problems (all p < 0.001). ADHD showed the highest overall emotional and behavioral burden, with 76% of participants scoring in the clinical range for both Internalizing and Total Problems and 60% for Externalizing Problems. Elevated internalizing difficulties characterized ASD and SLD, whereas children with DMD showed generally lower CBCL scores, although 26% fell within the clinical range for Internalizing Problems. Effect sizes were moderate to large (η² = 0.168–0.273), supporting the presence of both shared and disorder-specific emotional and behavioral patterns across heterogeneous developmental conditions. Conclusions: The findings highlight the heterogeneity of emotional–behavioral profiles across neurodevelopmental and neuromuscular conditions. The use of a common standardized assessment framework enabled the identification of both shared and disorder-specific patterns, supporting the potential value of a transdiagnostic approach to individualized assessment. Future longitudinal and multi-informant studies are warranted to clarify developmental trajectories and improve the identification of clinically meaningful emotional and behavioral needs across heterogeneous pediatric populations. Full article

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by out-of-frame variants in the DMD gene, resulting in dystrophin deficiency and progressive muscle degeneration. Beyond motor involvement, evidence links DMD to cognitive impairment and an emotional–behavioral (EB) burden, potentially related to the altered expression of brain dystrophin isoforms (Dp71, Dp140, Dp427). Objectives: To screen for major neurodevelopmental, cognitive and/or EB difficulties in a monocentric cohort of children with DMD. Methods: This cross-sectional study included 21 children with DMD. Neuropsychiatric difficulties were assessed using a multimodal psychometric battery. Cognitive, neurodevelopmental and genetic data were retrospectively collected and analyzed. Results: In the cohort, attention-deficit/hyperactivity disorder (ADHD)-related findings were predominantly inattentive, with 3/20 children (15.0%) scoring within the clinical range on at least one inattention subscale. For measures assessing autism spectrum disorder (ASD)-related features, scores above the normative cutoff emerged in 7/20 children (35.0%), while only 2/20 (10.0%) scored within the clinical range. Internalizing problems represented the predominant EB difficulties, and emotional dysregulation (ED) emerged as a plausible area of vulnerability in the cohort. Among the 11 of 21 children with available Full-Scale Intelligence Quotient (FSIQ) data, five (45.5%) had an FSIQ below 85. Of these, four of five (80.0%) presented the predicted Dp140−/Dp71+ brain dystrophin isoform expression pattern, whereas one of five (20.0%) presented the Dp140+/Dp71+ pattern. Conclusions: Children with DMD showed heterogeneous neuropsychiatric and cognitive features in the employed screening battery. These preliminary findings, if confirmed in larger cohorts, support the potential of a broader neuropsychiatric screening assessment to optimize care pathways. Full article

Background: The timing and efficacy of Achilles tendon lengthening (ATL) in Duchenne muscular dystrophy (DMD) remain controversial because indiscriminate surgery can accelerate ambulation loss. Case Description: This report presents a 5-year longitudinal comparative analysis (2021–2026) of monozygotic twins with identical genetic backgrounds (DMD exon 30–43 deletion) who received comparable rehabilitation and pharmacological management, including concurrent gene therapy in 2025. Twin A was managed conservatively with orthosis and subsequent serial casting for progressive equinus contracture, whereas Twin B underwent early bilateral ATL during transition to the non-ambulatory phase. Despite a temporary postoperative decline, Twin B demonstrated a more stable longitudinal motor trajectory, outperforming Twin A in gross motor function (Gross Motor Function Measure-88: 38.60% vs. 32.85% in 2026) by preserving residual standing and crawling dimensions. Longitudinal KIDSCREEN-52 assessments revealed a clinically meaningful improvement in psychological well-being in Twin B (+10.9 points) relative to Twin A. Conclusions: This single-pair twin case serves as a hypothesis-generating observation, highlighting a potential longitudinal association between early surgery and attenuated progressive motor decline within a multi-disciplinary care regimen. Given highly variable psychosocial outcomes, these trends cannot be directly attributed to surgery alone. When evaluating such orthopedic interventions, clinical decisions may benefit from looking beyond immediate gait metrics toward broader, long-term functional trends, though the relative contributions of concurrent therapies remain to be elucidated. Full article

Molecule Interacting with CasL 1 (MICAL1) is a flavoprotein monooxygenase that promotes filamentous actin (F-actin) depolymerization. Transcriptomic studies have linked MICAL1 downregulation to skeletal muscle atrophy and muscular dystrophy, yet its functional contribution to myogenesis remains unexplored. We found that MICAL1 protein increased progressively during myogenic differentiation of C2C12 cells, reaching a maximum on day 5 in parallel with myosin heavy chain (MyHC). siRNA-mediated MICAL1 silencing produced an ~1.7-fold accumulation of F-actin, while total β-actin protein remained unchanged, indicating a shift in the G-/F-actin equilibrium toward polymerization rather than altered actin expression. The accumulated F-actin reduced YAP1 phosphorylation, promoted its nuclear translocation, and increased the expression of the YAP1 target gene CTGF. MICAL1 depletion also enhanced myoblast proliferation: EdU incorporation and cell viability increased, and PCNA, CCNB1, and CCND1 protein expression was upregulated, while the cell cycle distribution shifted toward the G2/M phase, with a reciprocal loss in G0/G1. Concurrently, MICAL1 knockdown suppressed MyoD, Myogenin, and MyHC throughout differentiation and severely impaired myotube formation, with reductions in the fusion index, myotube area, and length. We conclude that MICAL1 is required for the proliferation-to-differentiation switch in myoblasts and that its activity restrains F-actin-driven YAP1 signaling to permit timely myogenic commitment. MICAL1 may therefore represent a candidate for further investigation in muscle-wasting diseases. Full article

Background: Duchenne muscular dystrophy (DMD) has, for the first time, several mutation-specific drugs in clinical use. Four exon-skipping antisense oligonucleotides and one adeno-associated virus (AAV) micro-dystrophin gene therapy carry US FDA approval, and one nonsense-readthrough agent (ataluren) holds a conditional European authorisation that has since been placed under review; ataluren has never been approved by the FDA. Regulatory approval, however, has not translated cleanly into demonstrable clinical benefit, and in resource-limited settings it has not translated into access at all. Methods: We compiled published efficacy estimates for each approved therapy: the EMBARK randomised trial for delandistrogene moxeparvovec (Elevidys), the STRIDE registry for ataluren, and the long-term extension studies of eteplirsen, golodirsen, viltolarsen and casimersen. We read these alongside mutation-spectrum and clinical data from a Kazakh DMD cohort (n = 34), one of the first Central Asian populations to be characterised systematically. Because these sources differ in design, population, endpoint and follow-up, the comparison is indirect and descriptive rather than pooled or statistical. On that basis we assembled three descriptive maps: biological versus clinical efficacy, eligibility versus access, and an order-of-magnitude estimate of cost per year of preserved ambulation. Results: Across the approved therapies, larger biological dystrophin restoration did not correspond to longer preservation of walking. We describe this as the absence of the expected positive association rather than as evidence of a negative one: the comparison rests on a small number of drugs whose values come from heterogeneous studies. We did not—and with these data could not—test it as a formal correlation. Ataluren, with roughly 2% dystrophin restoration, was associated with a longer reported delay in loss of ambulation than Elevidys, which restores 34–51% micro-dystrophin. In the Kazakh cohort, 26.5% of patients were biologically eligible for exon-skipping and 11.8% for ataluren, yet realistic access to any mutation-specific therapy was effectively zero as of April 2026. Our order-of-magnitude cost estimates ran from about $12,000 per additional year of ambulation for standard of care to about $1.3 million for AAV gene therapy, a hundredfold range that did not track clinical effect. Conclusions: We argue that the conventional priority ordering (gene therapy first, exon-skipping second, standard care as background) does not hold up when weighed against patient-relevant outcomes and cost, and may reasonably be inverted for resource-limited systems. This is our interpretation of an indirect comparison, not an evidence-based clinical recommendation. On that reading, the highest-value investments for Central Asia are early molecular diagnosis, universal access to glucocorticoids and specialised physiotherapy, and individual-import pathways for ataluren, while AAV gene therapy is, in our view, a lower near-term priority until its durability and safety data improve. Full article