Search Results (286)

Skeletal muscle regeneration requires a reliable source of myogenic progenitor cells capable of forming new fibers and creating a self-renewing satellite cell pool. Human induced pluripotent stem cell (hiPSC)-derived teratomas have emerged as a novel in vivo platform for generating skeletal myogenic progenitors, although in vivo studies to date have provided only an early single-time-point snapshot. In this study, we isolated a specific population of CD82⁺ ERBB3⁺ NGFR⁺ cells from human iPSC-derived teratomas and verified their long-term in vivo regenerative capacity following transplantation into NSG-mdx^4Cv mice. Transplanted cells engrafted, expanded, and generated human Dystrophin⁺ muscle fibers that increased in size over time and persisted stably long-term. A dynamic population of PAX7⁺ human satellite cells was established, initially expanding post-transplantation and declining moderately between 4 and 8 months as fibers matured. MyHC isoform analysis revealed a time-based shift from embryonic to neonatal and slow fiber types, indicating a slow progressive maturation of the graft. We further show that these progenitors can be cryopreserved and maintain their engraftment potential. Together, these findings give insight into the evolution of teratoma-derived human myogenic stem cell grafts, and highlight the long-term regenerative potential of teratoma-derived human skeletal myogenic progenitors. Full article

Background: The onset of cardiomyopathy in Duchenne muscular dystrophy (DMD) is insidious and poorly defined. We proposed integrated wall stress (iWS) as a marker of total left ventricular (LV) workload and tested whether the increased iWS represents early DMD cardiomyopathy. Methods: Peak systolic wall stress (PS-WS) was calculated in M-mode echocardiography with simultaneous blood pressure measurement. iWS was defined as a product of PS-WS and heart rate (HR) divided by 60 (=PS-WS/RR interval). We measured iWS in normal controls (CTRL), DMD with normal LV shortening fraction (%LVSF ≥ 30%) (DMD-A), and DMD with decreased %LVSF (<30%) (DMD-B). Results: 40 CTRL and 79 DMD patients were studied. Despite comparable %LVSF, both HR and iWS were significantly higher in DMD-A (n = 50) than in CTRL (p < 0.0001). iWS was significantly higher in DMD-B (n = 29) than in DMD-A (p < 0.0001) despite comparable HR. PS-WS was significantly higher in DMD-A than in CTRL and higher in DMD-B than in DMD-A, suggesting high HR is not a sole determinant of increased iWS in DMD-A compared with CTRL. In a longitudinal study in 35 DMD patients over 4.0 ± 2.0 years, iWS showed significant increase (p = 0.0062) alongside a significant decline in %LVSF (p < 0.0001). Conclusions: iWS significantly increased in DMD before %LVSF declined. The progressive increase of iWS in DMD is initially associated with increased HR and then with increased PS-WS. iWS may serve as a useful echocardiographic marker in identifying preclinical DMD cardiomyopathy. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. Despite major advancements in understanding its pathophysiology, there is still no curative treatment. This review provides an up-to-date overview of current and emerging therapeutic approaches—including antisense oligonucleotides, gene therapy, gene editing, corticosteroids, and histone deacetylases(HDAC) inhibitors—aimed at restoring dystrophin expression or mitigating disease progression. Special emphasis is placed on the importance of early diagnosis, the utility of genetic screening, and the innovations in pre-and post-natal testing. As the field advances toward personalized medicine, the integration of precision therapies with cutting-edge diagnostic technologies promises to improve both prognosis and quality of life for individuals with DMD. Full article

Background: Duchenne muscular dystrophy (DMD), which affects 1 in 3500 to 5000 newborn boys worldwide, is characterized by progressive skeletal muscle weakness and degeneration. The reduced muscle regeneration capacity presented by patients is associated with increased fibrosis. Satellite cells (SCs) are skeletal muscle stem cells that play an important role in adult muscle maintenance and regeneration. The absence or mutation of dystrophin in DMD is hypothesized to impair SC asymmetric division, leading to cell cycle arrest. Methods: To overcome the limited availability of biopsies from DMD patients, we used our 3D skeletal muscle organoid (SMO) system, which delivers a stable population of myogenic progenitors (MPs) in dormant, activated, and committed stages, to perform SMO cultures using three DMD patient-derived iPSC lines. Results: The results of scRNA-seq analysis of three DMD SMO cultures versus two healthy, non-isogenic, SMO cultures indicate reduced MP populations with constant activation and differentiation, trending toward embryonic and immature myotubes. Mapping our data onto the human myogenic reference atlas, together with primary SC scRNA-seq data, indicated a more immature developmental stage of DMD organoid-derived MPs. DMD fibro-adipogenic progenitors (FAPs) appear to be activated in SMOs. Conclusions: Our organoid system provides a promising model for studying muscular dystrophies in vitro, especially in the case of early developmental onset, and a methodology for overcoming the bottleneck of limited patient material for skeletal muscle disease modeling. Full article

Duchenne muscular dystrophy (DMD) is a severe inherited muscle-wasting disorder that is associated with severe morbidity and mortality globally. Current treatment options have improved the quality of life of patients, but these treatments are only palliative. There is a need for more DMD treatment options. Antisense oligonucleotide (ASO) therapies have emerged as a promising personalized treatment option for patient groups that possess specific mutations. A subset of these therapies can skip over frame-disrupting exons in the DMD gene and can partially restore dystrophin production for individuals with DMD. One novel exon skipping therapy currently being investigated is brogidirsen, an exon 44 that targets ASO using a novel dual-targeting approach. This article will provide an overview of brogidirsen’s history and current clinical trial developments. It will summarize how this investigational therapy compares with other pre-clinical and clinical trial-stage ASO therapies targeting exon 44. Current advances and challenges faced by RNA-based therapies will also be discussed. Overall, brogidirsen is a promising potential addition to existing DMD treatment options, with its clinical trial results showing expression levels above that of the maximum amount of dystrophin expression achieved by current FDA- and EMA-approved exon-skipping DMD therapies. Further research will be needed to determine its overall efficacy and ability to overcome the known limitations faced by other existing ASO therapies. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is often discussed in the literature with regard to physical impairments. This narrative review aims to show that living with DMD involves psychological, psychosocial, and cognitive aspects in addition to the well-known physical complications. Methods: Firstly, this review examines the main cognitive functions affecting subjects with DMD and the possible role of dystrophin gene mutations on the central nervous system. Secondly, it analyzes the comorbidity between DMD, neurodevelopmental disorders (autism spectrum disorders, attention-deficit/hyperactivity disorder, obsessive–compulsive disorder) and psychopathological traits (anxiety and/or depressive symptoms). Finally, the review addresses the relatively sparse literature investigating the positive aspects associated with the experience of DMD, like psychosocial resources, resilience, subjective well-being, positive individual and social functioning, and social support. Results: DMD has a significant impact on cognitive areas, probably due to dystrophin deficiency in the brain. The prevalence of neurodevelopmental comorbidities and psychopathological symptoms is also higher in people with DMD than in the general population. Despite these challenges, emerging studies highlight the role of psychosocial and environmental resources, including resilience and supportive social relations, in promoting a good quality of life and successful adaptation to disease progression. Conclusions: Early recognition of the above difficulties and strengths could ensure better care and promote an overall better quality of life for people with DMD and their families, physically, psychologically, and socially. Preclinical and clinical research is moving in the direction of finding new therapies, treatments, and psychosocial interventions to pursue these goals. Full article

Duchenne muscular dystrophy (DMD) manifests as a hereditary condition that diminishes muscular strength through the progressive degeneration of structural muscle tissue, which is brought about by deficiencies in the dystrophin protein required for the integrity of muscle cells. DMD is among four different types of dystrophinopathy disorders. Current studies have established that long non-coding RNAs (lncRNAs) play a significant role in determining the trajectory and overall prognosis of chronic musculoskeletal conditions. LncRNAs are different in terms of their lengths, production mechanisms, and operational modes, but they do not produce proteins, as their primary activity is the regulation of gene expression. This research synthesizes current literature on the role of lncRNAs in the regulation of myogenesis with a specific focus on certain lncRNAs leading to DMD increments or suppressing muscle biological functions. LncRNAs modulate skeletal myogenesis gene expression, yet pathological lncRNA function is linked to various muscular diseases. Some lncRNAs directly control genes or indirectly control miRNAs with positive or negative effects on muscle cells or the development of DMD. The research findings have significantly advanced our knowledge about the regulatory function of lncRNAs on muscle growth and regeneration processes and DMD diseases. Full article

Recent studies on myogenic satellite cells (SCs) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SCs in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. In this study, we isolated SCs from a porcine DMD model and age-matched wild-type (WT) piglets for comprehensive analysis. Using immunofluorescence, differentiation assays, traction force microscopy (TFM), RNA-seq, and label-free proteomic measurements, SCs behavior was characterized, and molecular changes were investigated. TFM revealed significantly higher average traction forces in DMD than WT SCs (90.4 ± 10.5 Pa vs. 66.9 ± 8.9 Pa; p = 0.0018). We identified 1390 differentially expressed genes and 1261 proteins with altered abundance in DMD vs. WT SCs. Dysregulated pathways uncovered by gene ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. Multi-omics factor analysis (MOFA) integrating transcriptomic and proteomic data, identified five factors accounting for the observed variance with an overall higher contribution of the transcriptomic data. Our findings suggest that SC impairments result from their inherent genetic abnormality rather than from environmental influences. The observed biological changes are intrinsic and not reactive to the pathological surrounding of DMD muscle. Full article

The stability of the sarcolemma is severely impaired in a series of genetic neuromuscular diseases defined as muscular dystrophies. These are characterized by the centralization of skeletal muscle syncytial nuclei, the replacement of muscle fibers with fibrotic tissue, the release of inflammatory cytokines, and the disruption of muscle protein homeostasis, ultimately leading to necrosis and loss of muscle functionality. A specific subgroup of muscular dystrophies is associated with genetic defects in components of the dystrophin–glycoprotein complex (DGC), which plays a crucial role in linking the cytosol to the skeletal muscle basement membrane. In these cases, dystrophin-associated proteins fail to correctly localize to the sarcolemma, resulting in dystrophy characterized by an uncontrolled increase in protein degradation, which can ultimately lead to cell death. In this review, we explore the role of intracellular degradative pathways—primarily the ubiquitin–proteasome and autophagy–lysosome systems—in the progression of DGC-linked muscular dystrophies. The DGC acts as a hub for numerous signaling pathways that regulate various cellular functions, including protein homeostasis. We examine whether the loss of structural stability within the DGC affects key signaling pathways that modulate protein recycling, with a particular emphasis on autophagy. Full article

Background: Three-dimensional skeletal muscle organoids (3D SkMO) are becoming of increasing interest for preclinical studies in Duchenne muscular dystrophy (DMD), provided that the used platform demonstrates the possibility to form functional and reproducible 3D SkMOs, to investigate on potential patient-related phenotypic differences. Methods: In this study, we employed fibrin-based 3D skeletal muscle organoids derived from immortalized myogenic precursors of DMD patients carrying either a stop codon mutation in exon 59 or a 48–50 deletion. We compared dystrophic lines with a healthy wild-type control (HWT) by assessing microtissue formation ability, contractile function at multiple timepoints along with intracellular calcium dynamics via calcium imaging, as well as expression of myogenic markers. Results: We found patient-specific structural and functional differences in the early stages of 3D SkMO development. Contractile force, measured as both single twitch and tetanic responses, was significantly lower in dystrophic 3D SkMOs compared to HWT, with the most pronounced differences observed at day 7 of differentiation. However, these disparities diminished over time under similar culturing conditions and in the absence of continuous nerve-like stimulation, suggesting that the primary deficit lies in delayed myogenic maturation, as also supported by gene expression analysis. Conclusions: Our results underline that, despite the initial maturation delay, DMD muscle precursors retain the capacity to form functional 3D SkMOs once this intrinsic lag is overcome. This suggests a critical role of dystrophin in early myogenic development, while contraction-induced stress and/or an inflammatory microenvironment are essential to fully recapitulate dystrophic phenotypes in 3D SkMOs. Full article

Abnormalities in X chromosomes, either numerical or structural, cause X-linked disorders, such as Duchenne muscular dystrophy (DMD). Recent molecular and cytogenetic techniques can help identify DMD gene mutations. The accurate diagnosis of Duchenne is crucial, directly impacting patient treatment management, genetics, and the establishment of effective prevention strategies. This review provides an overview of X chromosomal disorders affecting Duchenne and discusses how mutations in Dystrophin domains can impact detection accuracy. Firstly, the efficiency and use of cytogenetic and molecular techniques for the genetic diagnosis of Duchenne disease have, thus, become increasingly important. Secondly, artificial intelligence (AI) will be instrumental in developing future therapies by enabling the aggregation and synthesis of extensive and heterogeneous datasets, thereby elucidating underlying molecular mechanisms. However, despite advances in diagnostic technology, understanding the role of Dystrophin in Duchenne disease remains a challenge. Therefore, this review aims to synthesize this complex information to significantly advance the understanding of DMD and how it could affect patient care. Full article

Extracellular vesicles (EVs) are cell-derived lipid-bound vesicles divided into apoptotic bodies, microvesicles (MVs), and exosomes based on their biogenesis, release pathway, size, content, and functions. EVs are intercellular mediators that significantly affect muscle diseases such as Duchenne muscular dystrophy (DMD). DMD is a fatal X-linked disorder caused by mutations in the dystrophin gene, leading to muscle degeneration. Mdx mice are the most commonly used model to study the disease, and in this study, we phenotypically characterized plasma MVs from mdx mice by flow cytometry. Furthermore, we assessed the ability of plasma MVs to modulate muscle inflammation, damage, and/or regeneration by intramuscular injection of MVs from mdx mice into mdx or DBA/2 mice as a control. In both mouse lineages, platelets and erythrocytes were the primary sources of MVs, and CD3⁺ CD4⁺ MVs were observed only in mdx mice. We also observed that plasma MVs from mdx mice induced muscle damage in mdx mice but not in DBA/2 mice, while plasma MVs from DBA/2 mice did not induce muscle damage in either mouse lineage. These results indicate that plasma MVs from mdx are potentially pathogenic. However, this condition also depends on the muscular tissue status, which must be responsive due to active inflammatory or regenerative responses. Full article

Background: The transition from pediatric to adult care in Duchenne Muscular Dystrophy (DMD) is challenging due to the disease’s complexity and the need for lifelong, comprehensive management. In Romania, ongoing efforts aim to enhance multidisciplinary collaboration, though systemic barriers, such as fragmented healthcare services, persist. Nonsense mutations, including those in exon 30 described here, are often associated with more severe disease progression. Methods: We present the case of a 17-year-old Romanian DMD patient with a nonsense mutation in exon 30 of the dystrophin gene. The patient received multidisciplinary pediatric care addressing his medical needs, including neuromuscular, respiratory, cardiac, and orthopedic management. Transition readiness was assessed using the Transition Readiness Assessment Questionnaire (TRAQ), and the patient’s perspective on the process was documented. Results: Care followed international standards, but the disease progressed predictably, with gradual loss of ambulation, respiratory decline, and cardiac complications. The TRAQ revealed strengths in communication with healthcare providers but moderate confidence in self-management tasks. From the patient’s perspective, fragmented adult services and difficulty accessing specialized neuromuscular support remain major obstacles, underscoring the importance of early, structured transition planning and patient-centered approaches. Conclusions: Transitioning to adult services requires strong communication between pediatric and adult teams and integration of specialized care. Tailored follow-up plans ensure continuity of care and effective disease management. This case reflects broader needs in similar healthcare contexts, highlighting the necessity of robust transition frameworks to respond to patient-specific challenges and ultimately support long-term quality of life. Full article

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the progressive degeneration of skeletal and cardiac muscles due to the absence of dystrophin. Exon-skipping therapy is among the most promising approaches for treating DMD, with several antisense oligonucleotides (ASO) already approved by the FDA; however, their limited efficacy highlights substantial potential for further improvement. In this study, we evaluate the potential of combining ASO with valproic acid (VPA) to enhance dystrophin expression and improve functional outcomes in a murine model of DMD. Our results indicate that the ASO+VPA treatment significantly increases dystrophin restoration across various muscle tissues, with particularly pronounced effects observed in cardiac muscle, where levels are nearly doubled compared to ASO monotherapy. Additionally, we demonstrate significant improvements in functional outcomes in treated mdx mice. Our findings suggest that the combined ASO+VPA therapy holds promise as an effective therapeutic approach to ameliorate muscle function in DMD, warranting further exploration of its mechanistic pathways and long-term benefits. Full article

Duchenne Muscular Dystrophy (DMD) is a severe X-linked recessive disorder characterized by progressive muscle degeneration due to dystrophin deficiency. Cardiac involvement, particularly dilated cardiomyopathy, significantly impacts morbidity and mortality, typically manifesting after age 10. This case report presents a rare instance of early-onset cardiac involvement in a 3-year-old male with a confirmed deletion in exon 55 of the dystrophin gene. The patient developed dilated cardiomyopathy at 3 years and 8 months, with progressive left ventricular dysfunction despite early treatment with corticosteroids, ACE inhibitors, and beta-blockers. Genetic mechanisms and genotype–phenotype correlations related to cardiac involvement were reviewed, highlighting emerging therapies such as exon skipping, vamorolone, ifetroban, and rimeporide. Studies indicate that variants in exons 12, 14–17, 31–42, 45, and 48–49 are associated with more severe cardiac impairment. This case emphasizes the need for early, ongoing cardiac assessment and personalized treatment to address disease heterogeneity. While current DMD care standards improve survival, optimizing management through early intervention and novel therapies remains essential. Further research is needed to better understand genotype–phenotype correlations and improve cardiac outcomes for patients with DMD. Full article