Benfotiamine improves dystrophic pathology and exercise capacity in mdx mice by reducing inflammation and fibrosis.

Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease. Cycles of myofibre degeneration and regeneration are hallmarks of the disease where immune cells infiltrate to repair damaged skeletal muscle. Benfotiamine is a lipid soluble precursor to thiamine, shown clinically to reduce inflammation in diabetic related complications. We assessed whether benfotiamine administration could reduce inflammation related dystrophic pathology. Benfotiamine (10 mg/kg/day) was fed to male mdx mice (n = 7) for 15 weeks from 4 weeks of age. Treated mice had an increased growth weight (5-7 weeks) and myofibre size at treatment completion. Markers of dystrophic pathology (area of damaged necrotic tissue, central nuclei) were reduced in benfotiamine mdx quadriceps. Grip strength was increased and improved exercise capacity was found in mdx treated with benfotiamine for 12 weeks, before being placed into individual cages and allowed access to an exercise wheel for 3 weeks. Global gene expression profiling (RNAseq) in the gastrocnemius revealed benfotiamine regulated signalling pathways relevant to dystrophic pathology (Inflammatory Response, Myogenesis) and fibrotic gene markers (Col1a1, Col1a2, Col4a5, Col5a2, Col6a2, Col6a2, Col6a3, Lum) towards wildtype levels. In addition, we observed a reduction in gene expression of inflammatory gene markers in the quadriceps (Emr1, Cd163, Cd4, Cd8, Ifng). Overall, these data suggest that benfotiamine reduces dystrophic pathology by acting on inflammatory and fibrotic gene markers and signalling pathways. Given benfotiamine's excellent safety profile and current clinical use, it could be used in combination with glucocorticoids to treat DMD patients.

Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis.

Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and still largely unknown functions. Their biogenesis, which proceeds via a back-splicing reaction, is fairly well characterized, whereas their role in the modulation of physiologically relevant processes is still unclear. Here we performed expression profiling of circRNAs during in vitro differentiation of murine and human myoblasts, and we identified conserved species regulated in myogenesis and altered in Duchenne muscular dystrophy. A high-content functional genomic screen allowed the study of their functional role in muscle differentiation. One of them, circ-ZNF609, resulted in specifically controlling myoblast proliferation. Circ-ZNF609 contains an open reading frame spanning from the start codon, in common with the linear transcript, and terminating at an in-frame STOP codon, created upon circularization. Circ-ZNF609 is associated with heavy polysomes, and it is translated into a protein in a splicing-dependent and cap-independent manner, providing an example of a protein-coding circRNA in eukaryotes.

In dystrophic mdx hindlimb muscles where fibrosis is limited, versican haploinsufficiency transiently improves contractile function without reducing inflammation.

Versican is increased with inflammation and fibrosis, and is upregulated in Duchenne muscular dystrophy. In fibrotic diaphragm muscles from dystrophic mdx mice, genetic reduction of versican attenuated macrophage infiltration and improved contractile function. Versican is also implicated in myogenesis. Here, we investigated whether versican modulated mdx hindlimb muscle pathology, where inflammation and regeneration are increased but fibrosis is minimal. Immunohistochemistry and qRT-PCR were used to assess how fiber type and glucocorticoids (α-methylprednisolone) modify versican expression. To genetically reduce versican, female mdx and male versican haploinsufficient (hdf) mice were bred resulting in male mdx-hdf and mdx (control) pups. Versican expression, contractile function, and pathology were evaluated in hindlimb muscles. Versican immunoreactivity was greater in slow versus fast hindlimb muscles. Versican mRNA transcripts were reduced by α-methylprednisolone in soleus, but not in fast extensor digitorum longus, muscles. In juvenile (6-wk-old) mdx-hdf mice, versican expression was most robustly decreased in soleus muscles leading to improved force output and a modest reduction in fatiguability. These functional benefits were not accompanied by decreased inflammation. Muscle architecture, regeneration markers, and fiber type also did not differ between mdx-hdf mice and mdx littermates. Improvements in soleus contractile function were not retained in adult (20-wk-old) mdx-hdf mice. In conclusion, soleus muscles from juvenile mdx mice were most responsive to pharmacological or genetic approaches targeting versican; however, the benefits of versican reduction were limited due to low fibrosis. Preclinical matrix research in dystrophy should account for muscle phenotype (including age) and the interdependence between inflammation and fibrosis. NEW & NOTEWORTHY The proteoglycan versican is upregulated in muscular dystrophy. In fibrotic diaphragm muscles from mdx mice, versican reduction attenuated macrophage infiltration and improved performance. Here, in hindlimb muscles from 6- and 20-wk-old mdx mice, where pathology is mild, versican reduction did not decrease inflammation and contractile function improvements were limited to juvenile mice. In dystrophic mdx muscles, the association between versican and inflammation is mediated by fibrosis, demonstrating interdependence between the immune system and extracellular matrix.

BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disorder, characterised by progressive decline in skeletal muscle function due to the secondary consequences of dystrophin deficiency. Weakness extends to the respiratory musculature, and cardiorespiratory failure is the leading cause of death in men with DMD. Intermittent hypoxia has emerged as a potential therapy to counteract ventilatory insufficiency by eliciting long-term facilitation of breathing. Mechanisms of sensory and motor facilitation of breathing have been well delineated in animal models. Various paradigms of intermittent hypoxia have been designed and implemented in human trials culminating in clinical trials in people with spinal cord injury and amyotrophic lateral sclerosis. Application of therapeutic intermittent hypoxia to DMD is considered together with discussion of the potential barriers to progression owing to the complexity of this devastating disease. Notwithstanding the considerable challenges and potential pitfalls of intermittent hypoxia-based therapies for DMD, we suggest it is incumbent on the research community to explore the potential benefits in pre-clinical models. Intermittent hypoxia paradigms should be implemented to explore the proclivity to express respiratory plasticity with the longer-term aim of preserving and potentiating ventilation in pre-clinical models and people with DMD.

Treadmill running and mechanical overloading improved the strength of the plantaris muscle in the dystrophin-desmin double knockout (DKO) mouse.

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.

Reductions in functional muscle mass and ability to ambulate in Duchenne muscular dystrophy from ages 4 to 24 years.

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P < 0.0001 and r = 0.764, P < 0.0001 respectively). The age-associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non-ambulant subjects, suggesting a threshold of 18-22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. KEY POINTS: The non-invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non-ambulant patients. The difference in %MM between ambulant and non-ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM. The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability.

Definition of diaphragmatic sleep disordered breathing and clinical meaning in Duchenne muscular dystrophy.

BACKGROUND: Diaphragmatic sleep disordered breathing (dSDB) has been recently identified as sleep dysfunction secondary to diaphragmatic weakness in Duchenne muscular dystrophy (DMD). However, scoring criteria for the identification of dSDB are missing.This study aimed to define and validate dSDB scoring criteria and to evaluate whether dSDB severity correlates with respiratory progression in DMD. METHODS: Scoring criteria for diaphragmatic apnoea (dA) and hypopnoeas (dH) have been defined by the authors considering the pattern observed on cardiorespiratory polygraphy (CR) and the dSDB pathophysiology.10 sleep professionals (physiologists, consultants) blinded to each other were involved in a two-round Delphi survey to rate each item of the proposed dSDB criteria (Likert scale 1-5) and to recognise dSDB among other SDB. The scorers' accuracy was tested against the authors' panel.Finally, CR previously conducted in DMD in clinical setting were rescored and diaphragmatic Apnoea-Hypopnoea Index (dAHI) was derived. Pulmonary function (forced vital capacity per cent of predicted, FVC%pred), overnight oxygen saturation (SpO2) and transcutaneous carbon dioxide (tcCO2) were correlated with dAHI. RESULTS: After the second round of Delphi, raters deemed each item of dA and dH criteria as relevant as 4 or 5. The agreement with the panel in recognising dSDB was 81%, kappa 0.71, sensitivity 77% and specificity 85%.32 CRs from DMD patients were reviewed. dSDB was previously scored as obstructive. The dAHI negatively correlated with FVC%pred (r=-0.4; p<0.05). The total number of dA correlated with mean overnight tcCO2 (r 0.4; p<0.05). CONCLUSIONS: dSDB is a newly defined sleep disorder that correlates with DMD progression. A prospective study to evaluate dSDB as a respiratory measure for DMD in clinical and research settings is planned.

Different bone health progression patterns and early-stage risk marker in glucocorticoid-treated ambulatory Duchenne muscular dystrophy.

Fractures often cause irreversible harm in Duchenne muscular dystrophy (DMD). This study investigated the trajectory of bone mineral density (BMD) using group-based trajectory modeling and identified that BMD acts as an early-stage indicator of clinically significant bone fragility. The greater the early-stage BMD, the better the 4-year bone health outcome. PURPOSE: Most Duchenne muscular dystrophy (DMD) children suffer bone loss after long-term glucocorticoid (GC) exposure, which induces scoliosis and fragility fractures. To assess the BMD progression pattern and individual medical risk markers for these phenotypes in young ambulatory boys with DMD, and provide evidence-based suggestions for clinical management of bone health. METHODS: A retrospective longitudinal cohort study of 153 boys with DMD in West China Second University Hospital (2016-2023) was performed. Group-based trajectory modeling was used to study the BMD progression pattern, and potential predictors were further analyzed by logistic regression and survival analysis. RESULTS: One hundred and fifty-three participants were included, 71 of which had more than 3 BMD records. Three BMD trajectories were identified. Baseline BMD and age-started GC and were independent predictors of trajectory attribution. The median survival time of the first observation of low BMD in GC-treated DMD boys was 5.32 (95% CI 4.05-6.59) years, and a significant difference was tested (P < 0.001) among the three trajectory groups. CONCLUSION: BMD may serve as a novel early indicating marker for monitoring bone fragility for DMD. We proposed a bone health risk stratification through BMD progression trajectory that allows us to adapt the osteoporosis warning sign in DMD from a fixed threshold approach to a more individualized strategy, where baseline BMD and age of glucocorticoid initiation can provide an earlier prediction of bone loss. Better management of primary BMD may be able to delay or avoid the onset of adverse bone health outcomes in the fifth year in children with DMD.

Effectiveness of conservative non-pharmacological interventions in people with muscular dystrophies: a systematic review and meta-analysis.

INTRODUCTION: Management of muscular dystrophies (MD) relies on conservative non-pharmacological treatments, but evidence of their effectiveness is limited and inconclusive. OBJECTIVE: To investigate the effectiveness of conservative non-pharmacological interventions for MD physical management. METHODS: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched Medline, CINHAL, Embase, AMED and Cochrane Central Register of Controlled Trial (inception to August 2022). Effect size (ES) and 95% Confidence Interval (CI) quantified treatment effect. RESULTS: Of 31,285 identified articles, 39 studies (957 participants), mostly at high risk of bias, were included. For children with Duchenne muscular dystrophy (DMD), trunk-oriented strength exercises and usual care were more effective than usual care alone in improving distal upper-limb function, sitting and dynamic reaching balance (ES range: 0.87 to 2.29). For adults with Facioscapulohumeral dystrophy (FSHD), vibratory proprioceptive assistance and neuromuscular electrical stimulation respectively improved maximum voluntary isometric contraction and reduced pain intensity (ES range: 1.58 to 2.33). For adults with FSHD, Limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD), strength-training improved dynamic balance (sit-to-stand ability) and self-perceived physical condition (ES range: 0.83 to 1.00). A multicomponent programme improved perceived exertion rate and gait in adults with Myotonic dystrophy type 1 (DM1) (ES range: 0.92 to 3.83). CONCLUSIONS: Low-quality evidence suggests that strength training, with or without other exercise interventions, may improve perceived exertion, distal upper limb function, static and dynamic balance, gait and well-being in MD. Although more robust and larger studies are needed, current evidence supports the inclusion of strength training in MD treatment, as it was found to be safe.

Respiratory performance in Duchenne muscular dystrophy: Clinical manifestations and lessons from animal models.

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials.

Chronic N-acetyl cysteine treatment does not improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.

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.

Feasibility of virtual reality and comparison of its effectiveness to biofeedback in children with Duchenne and Becker muscular dystrophies.

INTRODUCTION/AIMS: The utilization of virtual reality (VR) and biofeedback training, while effective in diverse populations, remains limited in the treatment of Duchenne and Becker muscular dystrophies (D/BMD). This study aimed to determine the feasibility of VR in children with D/BMD and compare the effectiveness of VR and biofeedback in children with D/BMD. METHODS: The study included 25 children with D/BMD. Eight children in the control group participated in a routine follow-up rehabilitation program, while the remaining children were randomly assigned to the VR (n = 9) and biofeedback (n = 8) groups for a 12-week intervention. The following evaluations were performed before, during (week 6), and after treatment: Muscle pain and cramps, laboratory studies, muscle strength, timed performance, function (Motor Function Measurement Scale-32, Vignos, and Brooke Scales), and balance (Pediatric Functional Reach Test and Balance Master System). Motivation for rehabilitation was determined. RESULTS: The median ages were 9.00 (VR), 8.75 (biofeedback), and 7.00 (control) years. The study found no significant differences between groups in pretreatment assessments for most measures, except for tandem step width (p < .05). VR and biofeedback interventions significantly improved various aspects (pain intensity, cramp frequency, cramp severity, muscle strength, timed performance, functional level, and balance) in children with D/BMD (p < .05), while the conventional rehabilitation program maintained patients' current status without any changes. The study found VR and biofeedback equally effective, with VR maintaining children's motivation for rehabilitation longer (p < .05). DISCUSSION: The study showed that both VR and biofeedback appear to be effective for rehabilitation this population, but additional, larger studies are needed.

Quantitative ultrasonography reveals skeletal muscle abnormalities in carriers of DMD pathogenic variants.

INTRODUCTION/AIMS: Carriers of DMD pathogenic variants may become symptomatic and develop muscle-related manifestations. Despite that, few studies have attempted to characterize changes in the muscles of these carriers using imaging tools, particularly muscle ultrasound (MUS). The aim of this study was to compare lower limb MUS findings in carriers of DMD pathogenic variants (cDMD) vs healthy controls. METHODS: Twenty-eight women (15 cDMD and 13 controls) underwent clinical evaluation and MUS. We collected information about muscle-related symptoms and assessed muscle strength. MUS was performed by a single physician (blind to the genetic status of subjects). The following muscles were assessed: rectus femoris, sartorius, tibialis anterior, and medial gastrocnemius. For each site, we computed data on muscle thickness, cross-sectional area, sound attenuation index, and elastography. Between-group comparisons were assessed using nonparametric tests and p-values <.05 were deemed significant. RESULTS: None of the subjects had objective muscle weakness, but exercise intolerance/fatigue was reported by four cDMDs and only one control. Regarding MUS, sound attenuation indices were significantly higher among carriers for all muscles tested. Longitudinal and axial deep echo intensities for the rectus femoris and tibialis anterior were also higher in the cDMD group compared with controls. No significant between-group differences were noted for elastography values, muscle area, or mean echo intensities. DISCUSSION: cDMD have skeletal muscle abnormalities that can be detected using quantitative MUS. Further studies are needed to determine whether such abnormalities are related to muscle symptoms in these patients.

Sexual health and fertility in Duchenne muscular dystrophy-An exploratory study.

INTRODUCTION/AIMS: Recent clinical guidelines recommend that adolescents with Duchenne muscular dystrophy (DMD) who are on daily glucocorticoid treatment should be offered pubertal induction in order to ensure adult levels of sex hormones as they reach adulthood. However, it remains unclear how gonadal status, including androgen concentrations, impacts physical function and future fertility. The aim of this study was to give a voice to adults with DMD, exploring their perspectives around sexual health, hormone treatment, and fertility. METHODS: Qualitative data was collected from six adults with DMD through two online focus groups. Participants were recruited through Pathfinders Neuromuscular Alliance and Duchenne UK and invited to take part if they had DMD and were 18 years of age or older. Conversations were transcribed verbatim and an interpretivist paradigm was used with thematic analysis. RESULTS: The main themes identified were (1) the need for communication and information about sexual health, (2) dealing with the potential fear of rejection, (3) physical barriers to relationships including sex, (4) testosterone supplementation in DMD, and (5) parenthood and fertility. DISCUSSION: We recommend that clinicians work with young people with DMD individually, to explore the benefits of testosterone treatment for them and their personal sexual health needs. If they are offered treatment, this should always be accompanied by the opportunity for psychological support. This work highlights the need for further research to establish the role of testosterone supplementation in adults with DMD and its effects on fertility and the value of specific emotional and practical support for sexual health.

Diarylpropionitrile-stimulated ERß nuclear accumulation promotes MyoD-induced muscle regeneration in mdx mice by interacting with FOXO3A.

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor ß (ERß) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERß activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERß and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERß agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERß. DPN treatment augmented the nuclear accumulation of ERß and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERß-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERß during myogenesis.

Lessons for future clinical trials in adults with Becker muscular dystrophy: Disease progression detected by muscle magnetic resonance imaging, clinical and patient-reported outcome measures.

BACKGROUND AND PURPOSE: Because Becker muscular dystrophy (BMD) is a heterogeneous disease and only few studies have evaluated adult patients, it is currently still unclear which outcome measures should be used in future clinical trials. METHODS: Muscle magnetic resonance imaging, patient-reported outcome measures and a wide range of clinical outcome measures, including motor function, muscle strength and timed-function tests, were evaluated in 21 adults with BMD at baseline and at 9 and 18 months of follow-up. RESULTS: Proton density fat fraction increased significantly in 10/17 thigh muscles after 9 months, and in all thigh and lower leg muscles after 18 months. The 32-item Motor Function Measurement (MFM-32) scale (-1.3%, p = 0.017), North Star Ambulatory Assessment (-1.3 points, p = 0.010) and patient-reported activity limitations scale (-0.3 logits, p = 0.018) deteriorated significantly after 9 months. The 6-min walk distance (-28.7 m, p = 0.042), 10-m walking test (-0.1 m/s, p = 0.032), time to climb four stairs test (-0.03 m/s, p = 0.028) and Biodex peak torque measurements of quadriceps (-4.6 N m, p = 0.014) and hamstrings (-5.0 N m, p = 0.019) additionally deteriorated significantly after 18 months. At this timepoint, domain 1 of the MFM-32 was the only clinical outcome measure with a large sensitivity to change (standardized response mean 1.15). DISCUSSION: It is concluded that proton density fat fraction imaging of entire thigh muscles is a sensitive outcome measure to track progressive muscle fat replacement in patients with BMD, already after 9 months of follow-up. Finally, significant changes are reported in a wide range of clinical and patient-reported outcome measures, of which the MFM-32 appeared to be the most sensitive to change in adults with BMD.

Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

BACKGROUND AND PURPOSE: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes. METHODS: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022. Logistic regression, Cox proportional hazards models and survival analyses were conducted utilizing data from clinical records. RESULTS: In all, 112 individuals were included. Mean age was 23.4 ± 5.2 years and mean follow-up was 18.5 ± 5.5 years. At last assessment, 47.2% were on glucocorticoids; the mean dose of prednisone was 0.38 ± 0.13 mg/kg/day and of deflazacort 0.43 ± 0.16 mg/kg/day. At age 16 years, motor function limitations included using a manual wheelchair (89.7%), standing (87.9%), transferring from a wheelchair (86.2%) and turning in bed (53.4%); 77.5% had a peak cough flow <270 L/min, 53.3% a forced vital capacity percentage of predicted <50% and 40.3% a left ventricular ejection fraction <50%. Glucocorticoids after LOA reduced the risk and delayed the time to difficulties balancing in the wheelchair, loss of hand to mouth function, forced vital capacity percentage of predicted <30% and forced vital capacity <1 L and were associated with lower frequency of left ventricular ejection fraction <50%, without differences between prednisone and deflazacort. Glucocorticoid dose did not differ by functional, respiratory or cardiac status. CONCLUSION: Glucocorticoids after LOA preserve late-stage functional abilities, respiratory and cardiac function. It is suggested using functional abilities, respiratory and cardiac status at transition stages for adult services planning.

Lower urinary tract symptoms in children with Duchenne muscular dystrophy: An evaluation in terms of functional level, posture, and muscle strength.

AIM: To examine factors associated with lower urinary tract symptoms (LUTS) and lower urinary tract dysfunction (LUTD) in children with Duchenne muscular dystrophy (DMD). METHODS: This cross-sectional study included 45 individuals diagnosed with DMD between the ages of 5 and 18 years. LUTS were evaluated with the Dysfunctional Voiding and Incontinence Scoring System, functional levels with the Brooke Upper Extremity Functional Classification and the Vignos Scale, lumbar lordosis angle with a bubble inclinometer, pelvic inclination angles with a digital inclinometer, and muscle strength with a hand-held dynamometer. RESULTS: The mean age of the children was calculated as 9.00 ± 3.32 years, body weight as 31.10 ± 12.59 kg, and height as 125.87 ± 18.46 cm. LUTD was detected in 20 children (44.44%). There was an association between high LUTD severity and low strength of the following muscles: bilateral hip flexor (Dominant: r = -0.338, p = 0.023; nondominant: r = -0.411, p = 0.005), quadriceps femoris (Dominant: r = -0.445, p = 0.002; nondominant: r = -0.504, p < 0.001), elbow flexor (Dominant: r = -0.461, p = 0.001; nondominant: r = -0.455, p = 0.002), and elbow extensor (Dominant: r = -0.442, p = 0.002; nondominant: r = -0.450, p = 0.002). Upper extremity functionality level was significantly higher in the LUTD-negative group (p = 0.004). There was no relationship between lumbar lordosis and pelvic inclination angles and LUTS symptoms (p > 0.05). CONCLUSION: To provide the adequate care for bladder health in children with DMD, it is essential to focus on parameters that will increase functionality and independence in this population.

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.