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Biomolecules Oct 2023Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as... (Review)
Review
Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair. Here, we examine the pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies.
Topics: Humans; Muscular Dystrophy, Duchenne; Heart; Cardiomyopathies; Inflammation; Fibrosis
PubMed: 37892218
DOI: 10.3390/biom13101536 -
Journal of Cachexia, Sarcopenia and... Oct 2023Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their...
BACKGROUND
Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their accumulation remain poorly understood. Here, we explored the possibility of using beef cattle as a novel model for mechanistic studies of intramuscular adipogenesis and fibrogenesis.
METHODS
Skeletal muscle single-cell RNAseq was performed on three cattle breeds, including Wagyu (high IMF), Brahman (abundant IMC but scarce IMF), and Wagyu/Brahman cross. Sophisticated bioinformatics analyses, including clustering analysis, gene set enrichment analyses, gene regulatory network construction, RNA velocity, pseudotime analysis, and cell-cell communication analysis, were performed to elucidate heterogeneities and differentiation processes of individual cell types and differences between cattle breeds. Experiments were conducted to validate the function and specificity of identified key regulatory and marker genes. Integrated analysis with multiple published human and non-human primate datasets was performed to identify common mechanisms.
RESULTS
A total of 32 708 cells and 21 clusters were identified, including fibro/adipogenic progenitor (FAP) and other resident and infiltrating cell types. We identified an endomysial adipogenic FAP subpopulation enriched for COL4A1 and CFD (log2FC = 3.19 and 1.92, respectively; P < 0.0001) and a perimysial fibrogenic FAP subpopulation enriched for COL1A1 and POSTN (log2FC = 1.83 and 0.87, respectively; P < 0.0001), both of which were likely derived from an unspecified subpopulation. Further analysis revealed more progressed adipogenic programming of Wagyu FAPs and more advanced fibrogenic programming of Brahman FAPs. Mechanistically, NAB2 drives CFD expression, which in turn promotes adipogenesis. CFD expression in FAPs of young cattle before the onset of intramuscular adipogenesis was predictive of IMF contents in adulthood (R = 0.885, P < 0.01). Similar adipogenic and fibrogenic FAPs were identified in humans and monkeys. In aged humans with metabolic syndrome and progressed Duchenne muscular dystrophy (DMD) patients, increased CFD expression was observed (P < 0.05 and P < 0.0001, respectively), which was positively correlated with adipogenic marker expression, including ADIPOQ (R = 0.303, P < 0.01; and R = 0.348, P < 0.01, respectively). The specificity of Postn/POSTN as a fibrogenic FAP marker was validated using a lineage-tracing mouse line. POSTN expression was elevated in Brahman FAPs (P < 0.0001) and DMD patients (P < 0.01) but not in aged humans. Strong interactions between vascular cells and FAPs were also identified.
CONCLUSIONS
Our study demonstrates the feasibility of beef cattle as a model for studying IMF and IMC. We illustrate the FAP programming during intramuscular adipogenesis and fibrogenesis and reveal the reliability of CFD as a predictor and biomarker of IMF accumulation in cattle and humans.
Topics: Cattle; Humans; Animals; Mice; Aged; Adipogenesis; Reproducibility of Results; Muscle, Skeletal; Cell Differentiation; Muscular Dystrophy, Duchenne
PubMed: 37439037
DOI: 10.1002/jcsm.13292 -
International Journal of Molecular... Jul 2023Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on... (Review)
Review
Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on human disease. As a result, targeted splicing therapeutics have been developed, treating various diseases including spinal muscular atrophy and Duchenne muscular dystrophy. These advancements are very promising and emphasize the critical role of proper splicing in maintaining human health. Herein, we provide an overview of the current information on the composition and assembly of early splicing complexes-commitment complex and pre-spliceosome-and their association with human disease.
Topics: Humans; RNA Splicing; Spliceosomes; Muscular Dystrophy, Duchenne; Muscular Atrophy, Spinal; RNA Precursors
PubMed: 37511171
DOI: 10.3390/ijms241411412 -
Trends in Molecular Medicine Jul 2023Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children... (Review)
Review
Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.
Topics: Humans; AMP-Activated Protein Kinases; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Myotonic Dystrophy
PubMed: 37080889
DOI: 10.1016/j.molmed.2023.03.008 -
Neurology Mar 2024Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
METHODS
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
RESULTS
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
DISCUSSION
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov Identifier: NCT03439670.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.
Topics: Humans; Male; Biomarkers; Muscular Dystrophy, Duchenne; Prednisone; Pregnadienediols; Child, Preschool; Child
PubMed: 38335499
DOI: 10.1212/WNL.0000000000208112 -
Frontiers in Neurology 2023Sleep represents a major frontier both in clinical myology and as a new possibility for delivering treatment to neuromuscular patients since various neuromuscular cases... (Review)
Review
Sleep represents a major frontier both in clinical myology and as a new possibility for delivering treatment to neuromuscular patients since various neuromuscular cases present a variable degree of disordered sleep and such conditions should be diagnosed and prevented, i.e., sleep apnea and hypoxemia. These sleep disorders are present in dystrophinopathies and in various types of limb-girdle muscular dystrophies (LGMD). Excessive daytime sleepiness (EDS) is found in patients affected by spastic paraparesis or cerebellar ataxia but is rather common in both myotonic dystrophy type 1 and 2, and the correction of sleep disorders is therefore important to improve their daily quality of life (QoL) and consequent daily functioning. Other types of sleep dysfunction such as insomnia, a reduction in rapid eye movement (REM) sleep, loss of normal REM, or sleep-disordered breathing are found in other disorders including myasthenia, ataxias, spastic paraparesis, Charcot-Marie-Tooth disease, and neurogenic disorders, including polyneuropathies, and need appropriate treatment. Research done on this topic aims to incorporate a variety of nuances in metabolic disorders such as those in late-onset Pompe disease and are such as those in late-onset Pompe disease who are susceptible to enzyme replacement therapy (ERT). The overarching goal is to explore both the diagnosis and methodology of sleep-related problems in both genetic and acquired neuromuscular disorders. We also review the type of available treatment opportunities utilized to improve neuromuscular patients' QoL.
PubMed: 37456652
DOI: 10.3389/fneur.2023.1195302 -
American Journal of Human Genetics Jul 2023Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.
Topics: Humans; Amyotrophic Lateral Sclerosis; Motor Neurons; Muscular Dystrophies; Neurodegenerative Diseases; C9orf72 Protein; DNA Repeat Expansion; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37339631
DOI: 10.1016/j.ajhg.2023.05.014 -
Annals of Clinical and Translational... Dec 2023Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X-linked muscular disorder. Here, we aim to investigat the clinical...
OBJECTIVE
Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X-linked muscular disorder. Here, we aim to investigat the clinical involvement of skeletal, respiratory, cardiac, and central nervous systems in patients with BMD, as well as genotype-phenotype relationships.
METHODS
This nationwide cohort study investigated the clinical manifestations and genotype-phenotype relationships in 225 patients with BMD having in-frame deletion from 22 medical centers. The primary outcome was to elucidate the association of genotype with skeletal muscle, respiratory, cardiac, and central nervous system disorders. Descriptive statistics were used to analyze the data.
RESULTS
The average age of the subjects was 31.5 (range, 1-81) years. Initial symptoms of BMD were muscular (60%), followed by asymptomatic hypercreatine kinasemia (32.4%) and central nervous system disorders (5.3%). Gait disturbance was observed in 53.8% of patients and the average age at wheelchair introduction was 36.5 years. The ventilator introduction rate was 6.7% at an average age of 36.6 years. More than 30% of patients had an abnormal electrocardiogram and approximately 15% had heart failure symptoms. Cardiac function on echocardiography varied significantly among the patients. The frequencies of seizures and intellectual/developmental disability were 8.0% and 16.9%, respectively. Exon 45-47deletion (del) was the most common (22.6%), followed by exon 45-48del (13.1%). Patients with exon 45-49del patients demonstrated severe skeletal muscle damage. Patients with exon 45-47del and exon 45-55del patients did not require ventilator use.
INTERPRETATION
The study provides important prognostic information for patients and clinicians to establish therapy plans and to implement preventative medicine.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Muscular Dystrophy, Duchenne; Dystrophin; Cohort Studies; Genotype; Intellectual Disability; Heart Diseases; Central Nervous System Diseases
PubMed: 37882106
DOI: 10.1002/acn3.51925 -
Progress in Retinal and Eye Research Jul 2023Duchenne muscular dystrophy (DMD) is caused by X-linked inherited or de novo DMD gene mutations predominantly affecting males who develop early-onset muscle... (Review)
Review
Duchenne muscular dystrophy (DMD) is caused by X-linked inherited or de novo DMD gene mutations predominantly affecting males who develop early-onset muscle degeneration, severely affecting their quality of life and leading to reduced life expectancy. DMD patients may also develop proliferative retinopathy, cataract, ERG abnormalities, altered contrast sensitivity, color vision losses, and elevated flash detection thresholds during dark adaptation. Depending on the position of the genetic alteration in the large DMD gene, it is associated with a lack of the full-length dystrophin protein possibly with an additional loss of one or several other dystrophins, which are normally transcribed from internal promoters in retina and crystalline lens. During the last decades, the properties of the dystrophins have been characterized in patients with different genetic alterations and in genetic mouse models of DMD. The complex expression pattern of the dystrophins in photoreceptors, Müller glial cells and astrocytes, likely influences synaptic transmission, ionic balance and vascular integrity of the retina. However, the specific function of each retinal dystrophin remains largely unknown. This review describes the current knowledge on dystrophin expression, the putative molecular, structural, and physiological properties of retinal dystrophins, and the main clinical implications associated with the loss of dystrophins in DMD patients and mouse models. Current data and working hypotheses warrant future research on retinal dystrophins to increase our understanding of dystrophin function in the central nervous system in general and to unveil new retinal mechanisms and therapeutic avenues for retinal diseases.
Topics: Male; Mice; Animals; Dystrophin; Muscular Dystrophy, Duchenne; Quality of Life; Retina; Retinal Diseases
PubMed: 36404230
DOI: 10.1016/j.preteyeres.2022.101137