Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies.
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ABSTRACT:
SUBMITTER: Giordani L
PROVIDER: S-EPMC4755242 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:MicroRNA (miRNA) is a non-coding single-stranded RNA with a length of approximately 22 nucleotides and is mainly responsible for the regulation of gene expression at the post-transcriptional level. At present, miRNA have become potential biomarkers for various diseases such as tumor, leukemia, and nervous system disease. Muscle-specific microRNAs are enriched in the skeletal muscle of patients with Duchenne muscular dystrophy (DMD) and also play an important role in the pathogenesis of DMD. Creatine kinase has limited specificity in the diagnosis of DMD since its level is not significantly associated with disease severity, and therefore, it is of great clinical significance to explore whether muscle-specific microRNAs can be used as ideal biomarkers for DMD. This article reviews the research advances in this field.
| S-EPMC7389306 | biostudies-literature
Project description:BackgroundDuchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy without an effective treatment, caused by mutations in the DMD gene, leading to the absence of dystrophin. DMD results in muscle weakness, loss of ambulation, and death at an early age. Metabolomics studies in mdx mice, the most used model for DMD, reveal changes in metabolites associated with muscle degeneration and aging. In DMD, the tongue muscles exhibit unique behavior, initially showing partial protection against inflammation but later experiencing fibrosis and loss of muscle fibers. Certain metabolites and proteins, like TNF-α and TGF-β, are potential biomarkers for dystrophic muscle characterization.MethodsTo investigate disease progression and aging, we utilized young (1 month old) and old (21-25 months old) mdx and wild-type tongue muscles. Metabolite changes were analyzed using 1H nuclear magnetic resonance, while TNF-α and TGF-β were assessed using Western blotting to examine inflammation and fibrosis. Morphometric analysis was conducted to assess the extent of myofiber damage between groups.ResultsThe histological analysis of the mid-belly tongue showed no differences between groups. No differences were found between the concentrations of metabolites from wild-type or mdx whole tongues of the same age. The metabolites alanine, methionine, and 3-methylhistidine were higher, and taurine and glycerol were lower in young tongues in both wild type and mdx (p < 0.001). The metabolites glycine (p < 0.001) and glutamic acid (p = 0.0018) were different only in the mdx groups, being higher in young mdx mice. Acetic acid, phosphocreatine, isoleucine, succinic acid, creatine, and the proteins TNF-α and TGF-β had no difference in the analysis between groups (p > 0.05).ConclusionsSurprisingly, histological, metabolite, and protein analysis reveal that the tongue of old mdx remains partially spared from the severe myonecrosis observed in other muscles. The metabolites alanine, methionine, 3-methylhistidine, taurine, and glycerol may be effective for specific assessments, although their use for disease progression monitoring should be cautious due to age-related changes in the tongue muscle. Acetic acid, phosphocreatine, isoleucine, succinate, creatine, TNF-α, and TGF-β do not vary with aging and remain constant in spared muscles, suggesting their potential as specific biomarkers for DMD progression independent of aging.
| S-EPMC10500803 | biostudies-literature
Project description:Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for Duchenne muscular dystrophy (DMD) patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the serum levels of six muscle-specific miRNAs (miR-1/206/133/499/208a/208b, also known as myomiRs) were all elevated in DMD patients (P < 0.01). The receiver operating characteristic curves of circulating miR-206, miR-499, miR-208b, and miR-133 levels reflected strong separation between Becker's muscular dystrophy (BMD) and DMD patients (P < 0.05). miR-206, miR-499, and miR-208b levels were positively correlated with both age and type IIc muscle fiber content in DMD patients (2-6 years), indicating that they might represent the stage of disease as well as the process of regeneration. miR-499 and miR-208b levels were correlated with slow and fast fiber content and might reflect the ratio of slow to fast fibers in DMD patient (>6 years). Fibroblast growth factor, transforming growth factor-β, and tumor necrosis factor-α could affect the secretion of myomiRs, suggesting that circulating myomiRs might reflect the effects of cytokines and growth factors on degenerating and regenerating muscles. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for DMD diagnosis and disease progression.
| S-EPMC4121518 | biostudies-literature
Project description:Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed.
| S-EPMC4480531 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is a devastating disease that results in life-limiting complications such as loss of skeletal muscle function as well as respiratory and cardiac complications. Advanced therapeutics in pulmonary care have significantly reduced respiratory complication-related mortality, making cardiomyopathy the main determinant factor of survival. While there are multiple therapies such as the use of anti-inflammatory drugs, physical therapy, and ventilatory assistance targeted toward delaying the disease progression in DMD, a cure remains elusive. In the last decade, several therapeutic approaches have been developed to improve patient survival. These include small molecule-based therapy, micro-dystrophin gene delivery, CRISPR-mediated gene editing, nonsense readthrough, exon skipping, and cardiosphere-derived cell therapy. Associated with the specific benefits of each of these approaches are their individual risks and limitations. The variability in the genetic aberrations leading to DMD also limits the widespread use of these therapies. While numerous approaches have been explored to treat DMD pathophysiology, only a handful have successfully advanced through the preclinical stages. In this review, we summarize the currently approved as well as the most promising therapeutics undergoing clinical trials aimed toward treating DMD with a focus on its cardiac manifestations.
| S-EPMC10328182 | biostudies-literature
Project description:ObjectiveWe assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.MethodsGSL and QBA were obtained from 6 unilateral arm/leg muscles in 36 boys with DMD and 28 healthy boys (age = 2-14 years) for up to 2 years. We used a linear mixed effects model with random intercept and slope terms to compare trajectories of GSL, QBA, and functional assessments. We analyzed separately a subset of boys who initiated corticosteroids.ResultsCompared to healthy boys, increasing GSL in DMD boys >7.0 years old was first identified at 6 months (eg, anterior forearm slope difference of 1.16 arbitrary units/mo, p = 0.004, 95% confidence interval [CI] = 0.38-1.94); in boys ≤ 7 years old, differences in GSL first appeared at 12 months (0.82 arbitrary units/mo, p = 0.04, 95% CI = 0.075-1.565, in rectus femoris). QBA performed similarly to GSL (eg, DMD boys > 7 years old: 0.41dB/mo, p = 0.01, 95% CI = 0.096-0.72, in anterior forearm at 6 months). Ultrasound identified differences earlier than functional measures including 6-minute walk and supine-to-stand tests. However, neither QBA nor GSL showed an effect of corticosteroid initiation.InterpretationQBA performs similarly to GSL, and both appear more sensitive than functional assessments for detecting muscle deterioration in DMD. Additional studies will be required to determine whether quantitative muscle ultrasound can detect therapeutic efficacy. Ann Neurol 2017;81:633-640.
| S-EPMC5444989 | biostudies-literature
Project description:The interactions between nutrition and metabolism and skeletal muscle have long been known. Muscle is the major metabolic organ—it consumes more calories than other organs—and therefore, there is a clear need to discuss these interactions and provide some direction for future research areas regarding muscle pathologies. In addition, new experiments and manuscripts continually reveal additional highly intricate, reciprocal interactions between metabolism and muscle. These reciprocal interactions include exercise, age, sex, diet, and pathologies including atrophy, hypoxia, obesity, diabetes, and muscle myopathies. Central to this review are the metabolic changes that occur in the skeletal muscle cells of muscular dystrophy patients and mouse models. Many of these metabolic changes are pathogenic (inappropriate body mass changes, mitochondrial dysfunction, reduced adenosine triphosphate (ATP) levels, and increased Ca2+) and others are compensatory (increased phosphorylated AMP activated protein kinase (pAMPK), increased slow fiber numbers, and increased utrophin). Therefore, reversing or enhancing these changes with therapies will aid the patients. The multiple therapeutic targets to reverse or enhance the metabolic pathways will be discussed. Among the therapeutic targets are increasing pAMPK, utrophin, mitochondrial number and slow fiber characteristics, and inhibiting reactive oxygen species. Because new data reveals many additional intricate levels of interactions, new questions are rapidly arising. How does muscular dystrophy alter metabolism, and are the changes compensatory or pathogenic? How does metabolism affect muscular dystrophy? Of course, the most profound question is whether clinicians can therapeutically target nutrition and metabolism for muscular dystrophy patient benefit? Obtaining the answers to these questions will greatly aid patients with muscular dystrophy.
| S-EPMC6024668 | biostudies-literature
Project description:BACKGROUND:Duchenne Muscular Dystrophy is a severe, incurable disorder caused by mutations in the dystrophin gene. The disease is characterized by decreased muscle function, impaired muscle regeneration and increased inflammation. In a clinical context, muscle deterioration, is evaluated using physical tests and analysis of muscle biopsies, which fail to accurately monitor the disease progression. OBJECTIVES:This study aims to confirm and asses the value of blood protein biomarkers as disease progression markers using one of the largest longitudinal collection of samples. METHODS:A total of 560 samples, both serum and plasma, collected at three clinical sites are analyzed using a suspension bead array platform to assess 118 proteins targeted by 250 antibodies in microliter amount of samples. RESULTS:Nine proteins are confirmed as disease progression biomarkers in both plasma and serum. Abundance of these biomarkers decreases as the disease progresses but follows different trajectories. While carbonic anhydrase 3, microtubule associated protein 4 and collagen type I alpha 1 chain decline rather constantly over time, myosin light chain 3, electron transfer flavoprotein A, troponin T, malate dehydrogenase 2, lactate dehydrogenase B and nestin plateaus in early teens. Electron transfer flavoprotein A, correlates with the outcome of 6-minutes-walking-test whereas malate dehydrogenase 2 together with myosin light chain 3, carbonic anhydrase 3 and nestin correlate with respiratory capacity. CONCLUSIONS:Nine biomarkers have been identified that correlate with disease milestones, functional tests and respiratory capacity. Together these biomarkers recapitulate different stages of the disorder that, if validated can improve disease progression monitoring.
| S-EPMC7369103 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is a multisystemic disorder that affects 1:5000 boys. The severity of the phenotype varies dependent on the mutation site in the DMD gene and the resultant dystrophin expression profile. In skeletal muscle, dystrophin loss is associated with the disintegration of myofibers and their ineffective regeneration due to defective expansion and differentiation of the muscle stem cell pool. Some of these phenotypic alterations stem from the dystrophin absence-mediated serine-threonine protein kinase 2 (MARK2) misplacement/downregulation in activated muscle stem (satellite) cells and neuronal nitric oxide synthase loss in cells committed to myogenesis. Here, we trace changes in DNA methylation, histone modifications, and expression of regulatory noncoding RNAs during muscle regeneration, from the stage of satellite cells to myofibers. Furthermore, we describe the abrogation of these epigenetic regulatory processes due to changes in signal transduction in DMD and point to therapeutic treatments increasing the regenerative potential of diseased muscles based on this acquired knowledge.
| S-EPMC7814631 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy-receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy.
| S-EPMC3651321 | biostudies-literature