The relationship between lower urinary system symptoms and the level of independence and quality of life in children with Duchenne muscular dystrophy.

BACKGROUND: The purpose was to investigate the frequency of lower urinary tract symptoms (LUTS) and lower urinary tract dysfunction (LUTD) in Duchenne muscular dystrophy (DMD) and the relationship between these symptoms and independence and quality of life (QoL). METHODS: The cross-sectional study included children aged 5-18 years and diagnosed with DMD and their families. Data were collected using the Dysfunctional Voiding and Incontinence Scoring System (DVISS), the Barthel Index, and the Pediatric Quality of Life™ 3.0 Neuromuscular Module (PedsQL-NMM). RESULTS: The study was completed with 45 children with DMD. LUTS was found in 86.66% and LUTD was found in 44.44%. The most common symptom was holding maneuvers (62.22%). Other common symptoms were urinary urgency (55.55%), daytime urinary incontinence (46.66%), and enuresis (31.11%). There was a significant correlation of the DVISS with the level of independence and QoL (p < 0.05). Moreover, higher LUTS score was associated with lower Barthel and PedsQL-NMM scores. CONCLUSION: LUTS is a neglected condition, although it is frequently seen in children with DMD. CLINICAL TRIAL REGISTRATION: NCT05464446.

Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD. METHODS: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI. RESULTS: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001). DISCUSSION: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.

Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.

Ablation of the dystrophin Dp71f alternative C-terminal variant increases sarcoma tumour cell aggressiveness.

Alterations in Dp71 expression, the most ubiquitous dystrophin isoform, have been associated with patient survival across tumours. Intriguingly, in certain malignancies, Dp71 acts as a tumour suppressor, while manifesting oncogenic properties in others. This diversity could be explained by the expression of two Dp71 splice variants encoding proteins with distinct C-termini, each with specific properties. Expression of these variants has impeded the exploration of their unique roles. Using CRISPR/Cas9, we ablated the Dp71f variant with the alternative C-terminus in a sarcoma cell line not expressing the canonical C-terminal variant, and conducted molecular (RNAseq) and functional characterisation of the knockout cells. Dp71f ablation induced major transcriptomic alterations, particularly affecting the expression of genes involved in calcium signalling and ECM-receptor interaction pathways. The genome-scale metabolic analysis identified significant downregulation of glucose transport via membrane vesicle reaction (GLCter) and downregulated glycolysis/gluconeogenesis pathway. Functionally, these molecular changes corresponded with, increased calcium responses, cell adhesion, proliferation, survival under serum starvation and chemotherapeutic resistance. Knockout cells showed reduced GLUT1 protein expression, survival without attachment and their migration and invasion in vitro and in vivo were unaltered, despite increased matrix metalloproteinases release. Our findings emphasise the importance of alternative splicing of dystrophin transcripts and underscore the role of the Dp71f variant, which appears to govern distinct cellular processes frequently dysregulated in tumour cells. The loss of this regulatory mechanism promotes sarcoma cell survival and treatment resistance. Thus, Dp71f is a target for future investigations exploring the intricate functions of specific DMD transcripts in physiology and across malignancies.

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

Duchenne muscular dystrophy (DMD) is an X-linked inherited dystrophinopathy, with an incidence of 1 in 3,600 - 5,000 male live-born infants. The leading cause of death is often cardiomyopathy-related heart failure. Given the progressive nature of the disorder with involvement of skeletal muscle, respiratory and cardiac function, perioperative care remains challenging with an increased incidence of perioperative morbidity and mortality. Perioperative care can be challenging due to life-threatening perioperative adverse events related to associated end-organ effects, as well as sensitivity to various anesthetic agents, rhabdomyolysis, hyperkalemia, hyperthermia, and cardiac arrest. We present a 22-year-old DMD patient with left ventricular assisted device (LVAD), who presented for repair of both left distal femur and tibial diaphysis fractures. Anesthetic care included the unique combination of total intravenous anesthesia with dexmedetomidine and remimazolam combined with regional anesthesia including a supra-inguinal fascia iliaca block, saphenous nerve block, and popliteal nerve block. The basics of dystrophinopathies are presented, perioperative concerns discussed, and previous reports of the use of regional anesthesia as an adjunct to general anesthesia in adult and pediatric patients with DMD are reviewed.

Perspectives on and Experiences With Bullying From Youth With Neuromuscular Conditions.

Aim: To understand the bullying experiences of youth with neuromuscular conditions. Method: Fourteen participants with neuromuscular conditions (10 male; 10-19 years old) participated in semistructured interviews that were analyzed using inductive thematic analysis. Results: Four overarching themes were identified: (1) participants experienced stigma-based bullying; (2) participants exhibited resilience despite bullying victimization; (3) participants identified personally and theoretically helpful and unhelpful supports with regard to bullying; and (4) participants proposed bullying interventions. Interpretation: Individuals with neuromuscular conditions had unique experiences and perspectives on bullying. This qualitative study provides health care professionals with insight into the bullying experiences of patients with neuromuscular conditions. Findings highlight the role for formal and informal education to mitigate stigma-based bullying and increased opportunities for peer support as a protective factor against bullying.

Short-term treatment with Uncaria tomentosa aggravates the injury phenotype in mdx mice

Introduction: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) or UT is a medicinal plant with antiviral, antimutagenic, anti-inflammatory and antioxidant properties. Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene; this deficiency leads to sarcolemma instability, inflammation, muscle degeneration and fibrosis. Objective: Considering the importance of inflammation to dystrophy progression and the anti-inflammatory activity of UT, in the present study we evaluated whether oral administration of UT extract would ameliorate dystrophy in the mdx mice, a DMD model. Methods: Eight-week-old male mdx mice were submitted to 200 mg/kg body weight daily UT oral administration for 6 weeks. General histopathology was analysed, and muscle tumor necrosis factor α, transforming growth factor-ß, myostatin and osteopontin transcript levels were assessed. The ability of mice to sustain limb tension to oppose their gravitational force was measured. Data were analysed with the unpaired Student's t-test. Results: Morphologically, both untreated and UT-treated animals exhibited internalised nuclei, increased endomysial connective tissue and variations in muscle fibre diameters. Body weight and muscle strength were significantly reduced in the UT-treated animals. Blood creatine kinase was higher in UT-treated compared to untreated animals. In tibialis anterior, myostatin, transcript was more highly expressed in the UT-treated while in the diaphragm muscle, transforming growth factor-ß transcripts were less expressed in the UT-treated. Conclusion: While previous studies identified anti-inflammatory, antiproliferative and anticarcinogenic UT effects, the extract indicates worsening of dystrophic muscles phenotype after short-term treatment in mdx mice.

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in female mdx mice.

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA-binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.

Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.

BACKGROUND: Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD. METHODS: We generated double-transgenic mouse model (mdx;HMOX1Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function. RESULTS: HMOX1 induction caused a drop in SC pool in mdx;HMOX1Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx). CONCLUSIONS: Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.

Severe gastrointestinal problems in Duchenne muscular dystrophy: A case series.

Due to improved supportive care, survival of patients with Duchenne muscular dystrophy (DMD) has increased significantly. Consequently, new challenges emerge in adult patients with DMD. In clinical practice we increasingly see patients with serious, even life-threatening, gastrointestinal (GI) problems in advanced disease stages. Little is known about the longitudinal course of GI problems and the appropriate management. We present a case-series of six adult patients with DMD with (recurrent) GI problems that required hospital admission. The most prevalent reported serious GI symptoms were gastrointestinal pseudo-obstruction, (sub)ileus and gastric dilatation. Besides, an overview is presented of the therapeutic options for GI problems in DMD. The current study provides insight in possible treatment options, however, there is a clear need for more research and an integral guideline on treatment of GI problems in adult patients with DMD in order to reduce associated morbidity and mortality.

WRONGFUL BIRTH AND WRONGFUL LIFE LAWSUITS IN OBSTETRICS AND GYNECOLOGY.

Developments in preconception and prenatal technologies have led to undeniable advances in how healthcare providers screen and treat patients. Despite these advances, at any point errors can occur leading to misdiagnosis or a missed diagnosis. In some instances, the missed information can lead to the birth of a child with health issues where short of the error, the decision to avoid conception or terminate the pregnancy might have been made. When these lapses unfold, there exists the potential for a wrongful birth or wrongful life lawsuit to ensue. While these two actions are based on the same set of events, they are distinct legal claims with varying degrees of judicial permissibility. Global legal acceptability of wrongful birth and life lawsuits tends to resemble patterns in the United States. Analyzing prior wrongful birth and wrongful life claims can reveal common trends in events leading to these types of lawsuits, as well as an understanding of their potential outcomes. A familiarity with wrongful birth and wrongful life lawsuits demonstrates how these cases are a unique from other forms of prenatal or birth injury tort lawsuits and can provide insights to common shortcomings in clinical practice. Applying these lessons to clinical practice highlights key approaches towards limiting the risk of certain errors leading to wrongful birth and wrongful life lawsuits, with the goal of healthcare providers offering high quality healthcare.

Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development.

Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.

Pig models for translational Duchenne muscular dystrophy research.

Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked DMD gene, resulting in the absence of dystrophin, progressive muscle degeneration, and heart failure. Genetically tailored pig models resembling human DMD mutations recapitulate the biochemical, clinical, and pathological hallmarks of DMD with an accelerated disease progression compared to human patients. DMD pigs have been used to evaluate therapeutic concepts such as gene editing to reframe a disrupted DMD reading frame or the delivery of artificial chromosome vectors carrying the complete DMD gene. Moreover, DMD pigs have been instrumental in validating new diagnostic modalities such as multispectral optoacoustic tomography (MSOT) for non-invasive monitoring of disease progression. DMD pigs may thus help to bridge the gap between proof-of-concept studies in cellular or rodent models and clinical studies in patients.

Identification of hub genes and therapeutic siRNAs to develop novel adjunctive therapy for Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by various defects in the dystrophin gene and still no universal therapy. This study aims to identify the hub genes unrelated to excessive immune response but responsible for DMD progression and explore therapeutic siRNAs, thereby providing a novel treatment. METHODS: Top ten hub genes for DMD were identified from GSE38417 dataset by using GEO2R and PPI networks based on Cytoscape analysis. The hub genes unrelated to excessive immune response were identified by GeneCards, and their expression was further verified in mdx and C57 mice at 2 and 4 months (M) by (RT-q) PCR and western blotting. Therapeutic siRNAs were deemed as those that could normalize the expression of the validated hub genes in transfected C2C12 cells. RESULTS: 855 up-regulated and 324 down-regulated DEGs were screened from GSE38417 dataset. Five of the top 10 hub genes were considered as the candidate genes unrelated to excessive immune response, and three of these candidates were consistently and significantly up-regulated in mdx mice at 2 M and 4 M when compared with age-matched C57 mice, including Col1a2, Fbn1 and Fn1. Furthermore, the three validated up-regulated candidate genes can be significantly down-regulated by three rational designed siRNA (p < 0.0001), respectively. CONCLUSION: COL1A2, FBN1 and FN1 may be novel biomarkers for DMD, and the siRNAs designed in our study were help to develop adjunctive therapy for Duchenne muscular dystrophy.

Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.

Development and Pilot Validation of the DuMAND Checklist to Screen for Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND).

Background: Patients with Duchenne muscular dystrophy (DMD) face a higher risk of neurobehavioral problems, yet an international consensus on screening, assessing, and managing these difficulties is lacking. Objective: This report introduces the term Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND) to comprehensively cover the spectrum of neurobehavioral issues in DMD patients, including behavior, psychiatric disorders, and various cognitive, academic, and psychosocial deficits. To facilitate screening, the DuMAND Checklist, a 43-item tool with five subscales, was developed. Methods and results: DuMAND categories were derived through literature review, parent (48 mothers and 37 fathers), and expert (n = 28) input and feedback. The DuMAND Checklist subscales were developed iteratively, incorporating item selection, expert panel (n = 10) assessment for face validity, comprehensiveness, and a pilot validation study in a DMD sample (n = 20). DuMAND encompasses five categories: cognition and learning, social responsiveness, emotion regulation, externalizing behavior, and eating and sleeping. Preliminary validation of the DuMAND Checklist indicates acceptable-to-excellent internal consistency and construct validity. Conclusion: By introducing the DuMAND concept, this study seeks to inspire a consensus approach for screening, assessing, and managing neurobehavioral issues in DMD. Incorporating screening, using the DuMAND Checklist, in addition to medical follow-up will facilitate early intervention, addressing a critical gap in identification of neurobehavioral disorders in DMD. Future research is needed to further evaluate psychometric properties of the DuMAND Checklist and investigate the natural course of DuMAND. Highlights: -This report introduces the term Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND) to comprehensively cover the spectrum of neurobehavioral issues in DMD patients, including behavior, psychiatric disorders, and various cognitive, academic, and psychosocial deficits.-DuMAND encompasses five categories: cognition and learning, social responsiveness, emotion regulation, externalizing behavior, and eating and sleeping.-Preliminary validation of the DuMAND Checklist indicates acceptable-to-excellent internal consistency and construct validity.

Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models.

Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine-Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.

Cell-type specific effects of mineralocorticoid receptor gene expression suggest intercellular communication regulating fibrosis in skeletal muscle disease.

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD is caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles of myofiber degeneration and regeneration. Pathology is exacerbated by overactivation of infiltrating immune cells and fibroblasts, which leads to chronic inflammation and fibrosis. Mineralocorticoid receptors (MR), a type of nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on DMD cardiomyopathy and preclinical efficacy on skeletal muscle in DMD models. Methods: We have previously generated myofiber and myeloid MR knockout mouse models to dissect cell-specific functions of MR within dystrophic muscles. Here, we compared skeletal muscle gene expression from both knockouts to further define cell-type specific signaling downstream from MR. Results: Myeloid MR knockout increased proinflammatory and profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic gene in myeloid MR-knockout skeletal muscle and is a component of fibrosis in dystrophic skeletal muscle. Surprisingly, lysyl oxidase (Lox), canonically a collagen crosslinker, was increased in both MR knockouts, but did not localize to fibrotic regions of skeletal muscle. Lox localized within myofibers, including only a region of quadriceps muscles. Lysyl oxidase like 1 (Loxl1), another Lox family member, was increased only in myeloid MR knockout muscle and localized specifically to fibrotic regions. Discussion: This study suggests that MR signaling in the dystrophic muscle microenvironment involves communication between contributing cell types and modulates inflammatory and fibrotic pathways in muscle disease.

Dmd mdx mice have defective oligodendrogenesis, delayed myelin compaction and persistent hypomyelination.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin, a large cytosolic protein that links the cytoskeleton to extracellular matrix receptors in skeletal muscle. Aside from progressive muscle damage, many patients with DMD also have neurological deficits of unknown etiology. To investigate potential mechanisms for DMD neurological deficits, we assessed postnatal oligodendrogenesis and myelination in the Dmdmdx mouse model. In the ventricular-subventricular zone (V-SVZ) stem cell niche, we found that oligodendrocyte progenitor cell (OPC) production was deficient, with reduced OPC densities and proliferation, despite a normal stem cell niche organization. In the Dmdmdx corpus callosum, a large white matter tract adjacent to the V-SVZ, we also observed reduced OPC proliferation and fewer oligodendrocytes. Transmission electron microscopy further revealed significantly thinner myelin, an increased number of abnormal myelin structures and delayed myelin compaction, with hypomyelination persisting into adulthood. Our findings reveal alterations in oligodendrocyte development and myelination that support the hypothesis that changes in diffusion tensor imaging seen in patients with DMD reflect developmental changes in myelin architecture.

Observing the Clinical Course of Duchenne Muscular Dystrophy in Medicaid Real-World Healthcare Data.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a rare, severe progressive neuromuscular disease. Health insurance claims allow characterization of population-level real-world outcomes, based on observed healthcare resource use. An analysis of data specific to those with Medicaid insurance is presently unavailable. The objective was to describe the real-world clinical course of DMD based on claims data from Medicaid-insured individuals in the USA. METHODS: Individuals with DMD were identified from the MarketScan Multi-State Medicaid datasets (2013-2018). Diagnosis and procedure codes from healthcare claims were used to characterize the occurrence of DMD-relevant clinical observations; categories were scoliosis, cardiovascular-related, respiratory and severe respiratory-related, and neurologic/neuropsychiatric. Age-restricted analyses were conducted to focus on the ages at which DMD-relevant clinical observations were more likely to be captured, and to better understand the impact of both age and follow-up time. RESULTS: Of 2007 patients with DMD identified, median (interquartile range) age at index was 14 (9-20) years, and median follow-up was 3.1 (1.6-4.7) years. Neurologic and neuropsychiatric observations were most frequently identified, among 49.3% of the cohort; followed by cardiovascular (48.5%), respiratory (38.1%), scoliosis (36.3%), and severe respiratory (25.0%). Prevalence estimates for each category were higher when analyzed within age-restricted subgroups; and increased as follow-up time increased. CONCLUSIONS: This study is the first to use diagnosis and procedure codes from real-world Medicaid claims to document the clinical course in DMD. Findings were consistent with previously published estimates from commercially insured populations and clinical registries; and contribute to the expanding body of real-world evidence around clinical progression of patients with DMD.