Duchenne Muscular Dystrophy Muscle Research Articles

Regional anesthesia and muscle-wasting diseases in pediatrics: A focused educational review

The muscular dystrophies or muscle-wasting diseases include a diverse group of genetic disorders, which result in progressive degeneration of skeletal muscles, progressive muscle weakness, and comorbid multi-system involvement. Duchenne muscle dystrophy is the most common type of muscular dystrophy with a reported incidence of 1 in every 3500–6000 male live births in the United States. Given the progressive nature of these disorders, skeletal muscle weakness frequently progresses to loss of the ability to ambulate and perform functions of daily life. In addition to affecting the skeletal musculature, many muscular dystrophies have effects on both cardiac and smooth muscles. As respiratory muscles are one of the most frequently affected muscles in patients with muscular dystrophies, progressive respiratory insufficiency may occur with dependance on non-invasive forms of respiratory support. Given the progressive multi-system involvement associated with the muscular dystrophies, perioperative care and the use of general anesthetic agents and opioids may result in postoperative respiratory failure. In an effort to avoid the deleterious effects of anesthetic agents and opioids on hemodynamic and respiratory functions, regional anesthesia may be used as an adjunct to or instead of general anesthesia. This manuscript provides a literature review and educational summary regarding the use of regional anesthetic techniques in pediatric-aged patients with muscular dystrophies.

Golodirsen restores DMD transcript imbalance in Duchenne Muscular Dystrophy patient muscle cells

BackgroundAntisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability.MethodsHere, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053.ResultsWe confirm golodirsen’s selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD “transcript imbalance”, in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping.ConclusionAll these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition.

Stable oxidative posttranslational modifications alter the gating properties of RyR1.

The ryanodine receptor type 1 (RyR1) is a Ca2+ release channel that regulates skeletal muscle contraction by controlling Ca2+ release from the sarcoplasmic reticulum (SR). Posttranslational modifications (PTMs) of RyR1, such as phosphorylation, S-nitrosylation, and carbonylation are known to increase RyR1 open probability (Po), contributing to SR Ca2+ leak and skeletal muscle dysfunction. PTMs on RyR1 have been linked to muscle dysfunction in diseases like breast cancer, rheumatoid arthritis, Duchenne muscle dystrophy, and aging. While reactive oxygen species (ROS) and oxidative stress induce PTMs, the impact of stable oxidative modifications like 3-nitrotyrosine (3-NT) and malondialdehyde adducts (MDA) on RyR1 gating remains unclear. Mass spectrometry and single-channel recordings were used to study how 3-NT and MDA modify RyR1 and affect Po. Both modifications increased Po in a dose-dependent manner, with mass spectrometry identifying 30 modified residues out of 5035 amino acids per RyR1 monomer. Key modifications were found in domains critical for protein interaction and channel activation, including Y808/3NT in SPRY1, Y1081/3NT and H1254/MDA in SPRY2&3, and Q2107/MDA and Y2128/3NT in JSol, near the binding site of FKBP12. Though these modifications did not directly overlap with FKBP12 binding residues, they promoted FKBP12 dissociation from RyR1. These findings provide detailed insights into how stable oxidative PTMs on RyR1 residues alter channel gating, advancing our understanding of RyR1-mediated Ca2+ release in conditions associated with oxidative stress and muscle weakness.

385P Quantitative magnetic resonance of masticatory muscles in adolescents with Duchenne muscle dystrophy

385P Quantitative magnetic resonance of masticatory muscles in adolescents with Duchenne muscle dystrophy

Acute microtubule changes linked to DMD pathology are insufficient to impair contractile function or enhance contraction-induced injury in healthy muscle.

Duchenne muscular dystrophy (DMD) is marked by the genetic deficiency of the dystrophin protein in striated muscle whose consequence is a cascade of cellular changes that predispose the susceptibility to contraction injury central to DMD pathology. Recent evidence identified the proliferation of microtubules enriched in post-translationally modified tubulin as a consequence of dystrophins absence that increases the passive mechanics of the muscle fiber and the excess mechanotransduction elicited reactive oxygen species and calcium signals that promote contraction injury. Motivated by evidence that acutely normalizing the disease microtubule alterations reduced contraction injury in murine DMD muscle (mdx), here we sought the direct impact of these microtubule alterations independent of dystrophins absence and the multitude of other changes consequent to dystrophic disease. To this end we used acute pharmacologic (epithiolone-D, EpoD; 4 hours) or genetic (vashohibin-2 and small vasohibin binding protein overexpression via AAV9; 2 weeks) strategies to effectively model the proliferation of detyrosination enriched microtubules in the mdx muscle. Quantifying in vivo nerve evoked plantarflexor function we find no alteration in peak torque nor contraction kinetics in WT mice modeling these DMD relevant MT alterations. Quantifying the susceptibility to eccentric contraction injury we show EpoD treatment proffered a small but significant protection from contraction injury while VASH/SVBP had no discernable impact. We conclude that the disease dependent MT alterations act in concert with additional cellular changes to predispose contraction injury in DMD.

Combined General and Regional Anesthesia for a Patient With Duchenne Muscle Dystrophy With an Implanted Left Ventricular Assisted Device Undergoing Orthopedic Surgery

Combined General and Regional Anesthesia for a Patient With Duchenne Muscle Dystrophy With an Implanted Left Ventricular Assisted Device Undergoing Orthopedic Surgery

Leucyl-tRNA Synthetase Contributes to Muscle Weakness through Mammalian Target of Rapamycin Complex 1 Activation and Autophagy Suppression in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD), caused by loss-of-function mutations in the dystrophin gene, results in progressive muscle weakness and early fatality. Impaired autophagy is one of the cellular hallmarks of DMD, contributing to the disease progression. Molecular mechanisms underlying the inhibition of autophagy in DMD are not well understood. In the current study, the DMD mouse model mdx was used for the investigation of signaling pathways leading to suppression of autophagy. Mammalian target of rapamycin complex 1 (mTORC1) was hyperactive in the DMD muscles, accompanying muscle weakness and autophagy impairment. Surprisingly, Akt, a well-known upstream regulator of mTORC1, was not responsible for mTORC1 activation or the dystrophic muscle phenotypes. Instead, leucyl-tRNA synthetase (LeuRS) was overexpressed in mdx muscles compared with the wild type. LeuRS activates mTORC1 in a noncanonical mechanism that involves interaction with RagD, an activator of mTORC1. Disrupting LeuRS interaction with RagD by the small-molecule inhibitor BC-LI-0186 reduced mTORC1 activity, restored autophagy, and ameliorated myofiber damage in the mdx muscles. Furthermore, inhibition of LeuRS by BC-LI-0186 improved dystrophic muscle strength in an autophagy-dependent manner. Taken together, our findings uncovered a noncanonical function of the housekeeping protein LeuRS as a potential therapeutic target in the treatment of DMD.

SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes.

Overactivation of the transforming growth factor-β (TGFβ) signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, we investigated the role of SETDB1 (SET domain, bifurcated 1), a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGFβ induction, SETDB1 accumulates in the nuclei of healthy myotubes while being already present in the nuclei of DMD myotubes where TGFβ signaling is constitutively activated. Transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to down-regulation of TGFβ target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGFβ-driven fibrotic response in DMD muscles, providing an additional axis for therapeutic intervention.

Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers

Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by the absence of functional dystrophin. There are multiple ongoing clinical trials for DMD that are testing gene therapy treatments consisting of adeno-associated viral (AAV) vectors carrying miniaturized versions of dystrophin optimized for function, termed micro-dystrophins (μDys). Utrophin, the fetal homolog of dystrophin, has repeatedly been reported to be upregulated in human DMD muscle as a compensatory mechanism, but whether µDys displaces full-length utrophin is unknown. In this study, dystrophin/utrophin-deficient mice with transgenic overexpression of full-length utrophin in skeletal muscles were systemically administered low doses of either AAV6-CK8e-Hinge3-µDys (μDysH3) or AAV6-CK8e-μDys5 (μDys5). We used immunofluorescence to qualitatively assess the localization of μDys with transgenic utrophin and neuronal nitric oxide synthase (nNOS) in quadriceps muscles. μDys protein resulting from both gene therapies co-localized at myofiber membranes with transgenic utrophin. We also confirmed the sarcolemmal co-localization of nNOS with μDys5, but not with transgenic utrophin expression or μDysH3. Transgenic utrophin expression and μDys proteins produced from both therapies stabilize the dystrophin-glycoprotein complex as observed by sarcolemmal localization of β-dystroglycan. This study suggests that µDys gene therapy will likely not inhibit any endogenous compensation by utrophin in DMD muscle.

Advancing Biomarker Discovery and Therapeutic Targets in Duchenne Muscular Dystrophy: A Comprehensive Review.

Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases.

Qualitative and Quantitative Electrocardiogram Parameters in a Large Cohort of Children with Duchenne Muscle Dystrophy in Comparison with Age-Matched Healthy Subjects: A Study from South India.

Electrocardiography (ECG) remains an excellent screening tool for cardiac assessment in Duchenne muscular dystrophy (DMD), but an accurate interpretation requires comparison with age-matched healthy controls. We examined various ECG parameters in children with DMD, in comparison with age-matched controls. Standard 12-lead ECG tracings of serial patients were screened for quality and selected. Controls were healthy, age-matched school-going children. Both quantitative and qualitative ECG parameters were analyzed. After screening, ECGs from 252 patients with DMD (8.32 ± 3.12 years, 2-21 years) and ECGs from 151 age-matched healthy controls (9.72 ± 2.23, 4-19 years) were included. A significantly higher heart rate, shorter R-R interval, and taller R wave in V1 were seen across all age group of DMD in comparison to controls, with the difference increasing with age. While QT prolongation was seen in all age groups of DMD, QTc prolongation was seen only at 10 years or more. Incomplete right bundle branch block (RBBB) and pathological Q waves in inferolateral leads were exclusive in DMD, with the latter declining with age. Evidence for left ventricular (LV) pathology, such as tall R in V5/V6, increase in SV1 + RV6 height, and QRS complex duration, were seen only in the age group of 10 years or more. Stratification based on age and comparison with age-matched healthy subjects showed that several ECG parameters were influenced by age, and it also identified age-dependent evidence for LV pathology and QTc prolongation in DMD.

A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data.

We aimed to analyse genome-wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle-derived genome-wide RNA-sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single-sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA-Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, and single-nucleus RNA-sequencing (snRNA-seq) were performed in the remaining patients to validate the most correlated gene signature. Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P<0.05). The ssGSEA-Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs =0.744, P<0.001; MRI rs =0.718, P<0.001). Muscle qRT-PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median=25.007, P<0.001) and 12 BMD (median=5.654, P<0.001) patients were significantly higher than that in controls (median=1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs =0.883, P<0.001) and histological fibrofatty replacement (rs =0.804, P<0.001) and disease duration (rs =0.645, P<0.001) and North Star Ambulatory Assessment total scores (rs =-0.698, P<0.001). Muscle western blot analysis confirmed that both four DMD (median=2.958, P<0.05) and four BMD (median=1.959, P<0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median=1.068). The snRNA-seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro-adipogenic progenitors, satellite cells, and myoblasts. We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.

The Effect of Pressure Changes During Mechanical Insufflation-Exsufflation on Respiratory and Airway Physiology

Respiratory muscle weakness can impair cough function, leading to lower respiratory tract infections. These infections are an important contributor to morbidity and mortality in patients with neuromuscular disease. Mechanical insufflation-exsufflation (MIE) is used to augment cough function in these patients. Although MIE is widely used, there are few data to advise on the optimal technique. Since the introduction of MIE, the recommended pressures to be delivered have increased. There are concerns regarding the use of higher pressures and their potential to cause lung derecruitment and upper airway closure. What is the impact of high-pressure MIE (HP-MIE) on lung recruitment, respiratory drive, upper airway flow, and patient comfort, compared with low-pressure MIE (LP-MIE), in patients with respiratory muscle weakness? Clinically stable patients using domiciliary MIE with respiratory muscle weakness secondary to Duchenne muscle dystrophy, spinal cord injury, or long-term tracheostomy ventilation received LP-MIE (30/-30cm H2O) and HP-MIE (60/-60cm H2O) in a random sequence. Lung recruitment, neural respiratory drive, and cough peak expiratory flow were measured throughout, and patients reported comfort and breathlessness following each intervention. A total of 29 patients (10 with Duchenne muscle dystrophy, eight with spinal cord injury, and 11 with long-term tracheostomy ventilation) were included in this study. HP-MIE augmented cough peak expiratory flow compared with LP-MIE (mean cough peak expiratory flow HP-MIE 228 ± 81 L/min vsLP-MIE 179 ± 67 L/min; P= .0001) without any significant change in lung recruitment, neural respiratory drive, or patient-reported breathlessness. However, in patients with more pronounced respiratory muscle weakness, HP-MIE resulted in an increased rate of upper airway closure and patient discomfort that may have an impact on clinical efficacy. HP-MIE did not lead to lung derecruitment or breathlessness compared with LP-MIE. However, it was poorly tolerated in individuals with advanced respiratory muscle weakness. HP-MIE generates more upper airway closure than LP-MIE, which may be missed if cough peak expiratory flow is used as the sole titration target. ClinicalTrials.gov; No.: NCT02753959; URL: www. gov.

Mimicking sarcolemmal damage in vitro: a contractile 3D model of skeletal muscle for drug testing in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disease diagnosed in childhood. It is a progressive and wasting disease, characterized by a degeneration of skeletal and cardiac muscles caused by the lack of dystrophin protein. The absence of this crucial structural protein leads to sarcolemmal fragility, resulting in muscle fiber damage during contraction. Despite ongoing efforts, there is no cure available for DMD patients. One of the primary challenges is the limited efficacy of current preclinical tools, which fail in modeling the biological complexity of the disease. Human-based three-dimensional (3D) cell culture methods appear as a novel approach to accelerate preclinical research by enhancing the reproduction of pathophysiological processes in skeletal muscle. In this work, we developed a patient-derived functional 3D skeletal muscle model of DMD that reproduces the sarcolemmal damage found in the native DMD muscle. These bioengineered skeletal muscle tissues exhibit contractile functionality, as they responded to electrical pulse stimulation. Sustained contractile regimes induced the loss of myotube integrity, mirroring the pathological myotube breakdown inherent in DMD due to sarcolemmal instability. Moreover, damaged DMD tissues showed disease functional phenotypes, such as tetanic fatigue. We also evaluated the therapeutic effect of utrophin upregulator drug candidates on the functionality of the skeletal muscle tissues, thus providing deeper insight into the real impact of these treatments. Overall, our findings underscore the potential of bioengineered 3D skeletal muscle technology to advance DMD research and facilitate the development of novel therapies for DMD and related neuromuscular disorders.

Characterization of the Ang/Tie2 Signaling Pathway in the Diaphragm Muscle of DMD Mice.

In Duchenne muscular dystrophy (DMD), angiogenesis appears to be attenuated. Local administration of angiopoietin 1 (Ang1) has been shown to reduce inflammation, ischemia, and fibrosis in DMD mice. Ang1 is a vital vascular stabilizing factor that activates the endothelial cell receptor Tie2, leading to downstream pro-survival PI3K/Akt pathway activation and eNOS phosphorylation. In this study, we aimed to characterize the Ang/Tie2 signaling pathway within the diaphragm muscle of mouse models of DMD. Utilizing ELISA, immunoblots, and RT-qPCR, we demonstrated that Ang1 was downregulated, while the antagonist angiopoietin 2 (Ang2) was upregulated, leading to a decreased Ang1/Ang2 ratio. This correlated with a reduction in the phosphorylated Tie2/total Tie2 ratio. Interestingly, no significant differences in Akt or eNOS phosphorylation were observed, although DMD murine models did have elevated total Akt protein concentrations. These observations suggest that Ang1/Tie2 signaling may be dysregulated in the diaphragm muscle of DMD and further investigations may lead to new therapeutic interventions for DMD.

A cellular and molecular spatial atlas of dystrophic muscle

Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.

Production of Duchenne muscular dystrophy cellular model using CRISPR-Cas9 exon deletion strategy.

Duchenne Muscular Dystrophy (DMD) is a progressive muscle wasting disorder caused by loss-of-function mutations in the dystrophin gene. Although the search for a definitive cure has failed to date, extensive efforts have been made to introduce effective therapeutic strategies. Gene editing technology is a great revolution in biology, having an immediate application in the generation of research models. DMD muscle cell lines are reliable sources to evaluate and optimize therapeutic strategies, in-depth study of DMD pathology, and screening the effective drugs. However, only a few immortalized muscle cell lines with DMD mutations are available. In addition, obtaining muscle cells from patients also requires an invasive muscle biopsy. Mostly DMD variants are rare, making it challenging to identify a patient with a particular mutation for a muscle biopsy. To overcome these challenges and generate myoblast cultures, we optimized a CRISPR/Cas9 gene editing approach to model the most common DMD mutations that include approximately 28.2% of patients. GAP-PCR and sequencing results show the ability of the CRISPR-Cas9 system to efficient deletion of mentioned exons. We showed producing truncated transcript due to the targeted deletion by RT-PCR and sequencing. Finally, mutation-induced disruption of dystrophin protein expression was confirmed by western blotting. All together, we successfully created four immortalized DMD muscle cell lines and showed the efficacy of the CRISPR-Cas9 system for the generation of immortalized DMD cell models with the targeted deletions.

Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice

Restoration of brain dystrophin using tricyclo-DNA ASOs restores neurobehavioral deficits in DMD mice

Downregulation of Dystrophin Expression Occurs across Diverse Tumors, Correlates with the Age of Onset, Staging and Reduced Survival of Patients.

Altered dystrophin expression was found in some tumors and recent studies identified a developmental onset of Duchenne muscular dystrophy (DMD). Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin alteration evokes related outcomes. Transcriptomic, proteomic, and mutation datasets from fifty tumor tissues and matching controls (10,894 samples) and 140 corresponding tumor cell lines were analyzed. Interestingly, dystrophin transcripts and protein expression were found widespread across healthy tissues and at housekeeping gene levels. In 80% of tumors, DMD expression was reduced due to transcriptional downregulation and not somatic mutations. The full-length transcript encoding Dp427 was decreased in 68% of tumors, while Dp71 variants showed variability of expression. Notably, low expression of dystrophins was associated with a more advanced stage, older age of onset, and reduced survival across different tumors. Hierarchical clustering analysis of DMD transcripts distinguished malignant from control tissues. Transcriptomes of primary tumors and tumor cell lines with low DMD expression showed enrichment of specific pathways in the differentially expressed genes. Pathways consistently identified: ECM-receptor interaction, calcium signaling, and PI3K-Akt are also altered in DMD muscle. Therefore, the importance of this largest known gene extends beyond its roles identified in DMD, and certainly into oncology.

Vascular therapy for Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy (DMD) is a progressive disease characterized by the wasting of the muscles that eventually lead to difficulty moving and, ultimately, premature death from heart and respiratory complications. DMD deficiency is caused by mutations in the gene encoding dystrophin, which prevents skeletal muscle, cardiac muscle, and other cells from producing the functional protein. Located on the cytoplasmic face of the plasma membrane of muscle fibers, dystrophin serves as a component of the dystrophin glycoprotein complex (DGC), mechanically reinforces the sarcolemma, and stabilizes the DGC, preventing it from contraction-mediated muscle degradation. In DMD muscle, dystrophin deficiency leads to progressive fibrosis, myofiber damage, chronic inflammation, and dysfunction of the mitochondria and muscle stem cells. Currently, DMD is incurable, and treatment involves the administration of glucocorticoids in order to delay disease progression. In the presence of developmental delay, proximal weakness, and elevated serum creatine kinase levels, a definitive diagnosis can usually be made after an extensive review of the patient's history and physical examination, as well as confirmation through muscle biopsy or genetic testing. Current standards of care include the use of corticosteroids to prolong ambulation and delay the onset of secondary complications, including respiratory muscle and cardiac functions. However, different studies have been carried out to show the relationship between vascular density and impaired angiogenesis in the pathogenesis of DMD. Several recent studies on DMD management are vascular targeted and focused on ischemia as a culprit for the pathogenesis of DMD. This review critically discusses approaches-such as modulation of nitric oxide (NO) or vascular endothelial growth factor (VEGF)-related pathways-to attenuate the dystrophic phenotype and enhance angiogenesis.