MDX

Histologic separation of injury, T cell-mediated rejection, or antibody-mediated rejection in allograft heart biopsies is difficult. A critical review of publications was performed to evaluate the caveats of using molecular diagnostics (MDX) to distinguish between these entities. Typically, only 1 to 2 fragments of unknown histologic appearance are evaluated. Archetype and molecular classifier analyses use gene lists derived from histologic labels and associated reproducibility issues influence the accuracy of the derived MDX classes...

This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency...

BACKGROUND: ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment...

BACKGROUND: A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) upregulation contributes to the atrial electrical remodelling that underpins human and experimental atrial fibrillation (AF). By contrast, patients with Duchenne Muscular Dystrophy (DMD), who lack dystrophin and NOS1 and, at least in the skeletal muscle, have raised miR-31 expression, do not have increase susceptibility to AF in the absence of left ventricular (LV) dysfunction...

Duchenne muscular dystrophy (DMD) is characterised by fibrotic tissue deposition in skeletal muscle. We assessed the role of periostin in fibrosis using mdx mice, an established DMD murine model, for which we conducted a thorough examination of periostin expression over a year. RNA and protein levels in diaphragm (DIA) muscles were assessed and complemented by a detailed histological analysis at 5 months of age. In dystrophic DIAs, periostin ( Postn) mRNA expression significantly exceeded that seen in wildtype controls at all timepoints analysed, with the highest expression at 5 months of age ( p < 0...

BACKGROUND: Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is traditionally used as a diagnostic biomarker of DMD, but its potential as a robust pharmacodynamic (PD) biomarker is difficult due to the wide variability seen within the same participant over time...

It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice...

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+ ) cycling related to early-stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age-dependent DCM...

Duchenne muscular dystrophy (DMD), a severe X-linked inherited neuromuscular disease, has a high prevalence of obesity. Obesity exacerbates muscle damage and results in adverse clinical outcomes. Preventing obesity helps DMD patients delay disease progression and improve quality of life. Astaxanthin (AX) is a kind of carotenoid which has antioxidant and anti-adipogenesis effects. In this study, male C57BL/10ScSnDmdmdx/J mice were fed with a normal diet, a high-fat diet (HFD), and an HFD containing AX for 16 weeks, respectively...

In this study we conducted the first investigation to assess the efficacy of a novel therapeutic antibody developed to target annexin-A1 (ANXA1). ANXA1 is an immunomodulatory protein which has been shown to be overexpressed in, and promote the development and progression of, several cancer types. In particular, high ANXA1 expression levels correlate with poorer overall survival in pancreatic and triple-negative breast cancers, two cancers with considerable unmet clinical need. MDX-124 is a humanised IgG1 monoclonal antibody which specifically binds to ANXA1 disrupting its interaction with formyl peptide receptors 1 and 2 (FPR1/2)...

Insulin-like growth factor-1 (IGF-1) has been considered as a therapeutic agent for muscle wasting conditions including Duchenne muscular dystrophy as it stimulates muscle regeneration, growth and function. Several preclinical and clinical studies have been conducted to show the therapeutic potential of IGF-1, however, delivery issues, short half-life and isoform complexity have impose challenges. Antisense oligonucleotides (AONs) are able to downregulate target proteins by interfering with their transcripts...

BACKGROUND: Exercise therapy can improve muscle mass, strengthen muscle and cardiorespiratory function, and may be an excellent adjunctive treatment option for Duchenne muscular dystrophy. METHODS: This article investigates the effects of 10 weeks of treadmill training on skeletal muscle in control and mdx mice. Hematoxylin and eosin (H&E) staining was used to detect the morphometry of skeletal muscle; the grip strength test, suspension test, and rotarod test were used to detect limb muscle strength of mice, and Aurora Scientific Instruments were used to detect in vivo Muscle Stimulation Measuring Maximum Force of pre-fatigue and post-fatigue...

Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology...

Although progress had been made in clarifying the pathogenesis of Duchenne muscular dystrophy (DMD), significant work needs to be done to unveil detailedly the cellular and molecular mechanisms associated with DMD for developing efficacious treatments. To identify the hub genes and dysregulated pathways in the progression of DMD, GSE13608, GSE38417 and GSE109178 mRNA microarray datasets were downloaded from Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) between DMD and normal tissues were obtained, and function enrichment analyses were carried out...

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue, ALY688-SR, remodels the diaphragm of D2...

(+)-Negamycin, which is a dipeptide-like antibiotic containing a hydrazide structure, exhibits readthrough activity, resulting in the restoration of dystrophin in the mdx mouse model of Duchenne muscular dystrophy (DMD). In our previous structure-activity relationship study of negamycin, we found that its natural analogue 3- epi -deoxynegamycin (TCP-107), without antimicrobial activity, showed a higher readthrough activity than negamycin. In this study, we designed and synthesized cyclopropane-based conformationally restricted derivatives of TCP-107 and evaluated their readthrough activity in the cell-based reporter assay against a TGA-type mutation derived from DMD...

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a severe muscle illness caused by mutations in the gene encoding for the intracellular protein dystrophin. A major source for arrhythmia vulnerability in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for human DMD, we previously reported that the lack of dystrophin causes a significant loss of peak Na current (INa ) in ventricular cardiomyocytes...

Heart disease is a leading cause of death in patients with Duchenne muscular dystrophy (DMD), characterized by the progressive replacement of contractile tissue with scar tissue. Effective therapies for dystrophic cardiomyopathy will require addressing the disease prior to the onset of fibrosis, however the mechanisms of the early disease are poorly understood. To understand the pathophysiology of DMD we perform detailed functional assessment of cardiac function of the mdx mouse, a model of DMD. These studies use a combination of functional, metabolomic, and spectroscopic approaches to fully characterize the contractile, energetic, and mitochondrial function of beating hearts...

The work shows the effect of the metabolic modulator uridine on the functioning and ultrastructure of heart mitochondria in dystrophin-deficient mdx mice. Intraperitoneal administration of uridine (30 mg/kg/day for 28 days) improved K+ transport and increased its content in the heart mitochondria of mdx mice to the level of wild-type animals. This was accompanied by a significant decrease in the level of malondialdehyde and an increase in the number of mitochondria in the heart of mdx mice. At the same time, uridine did not affect the hyperfunctionality of mitochondria in mdx mice, which manifested in an increase in the calcium retention capacity...

PURPOSE: Reactive oxygen species and mitochondrial dysfunction play a crucial role in the pathophysiology of Duchenne muscular dystrophy (DMD). The light-emitting diode therapy (LEDT) showed beneficial effects on the dystrophic muscles. However, the mechanisms of this therapy influence the molecular pathways in the dystrophic muscles, particularly related to antioxidant effects, which still needs to be elucidated. The current study provides muscle cell-specific insights into the effect of LEDT, 48 h post-irradiation, on oxidative stress and mitochondrial parameters in the dystrophic primary muscle cells in culture...