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Hellenic Journal of Cardiology : HJC =... 2023Duchenne muscular dystrophy is a fatal X-linked recessive disease affecting approximately 1 in 3500 births. It is characterized by a genetic lack of dystrophin, which is... (Review)
Review
Duchenne muscular dystrophy is a fatal X-linked recessive disease affecting approximately 1 in 3500 births. It is characterized by a genetic lack of dystrophin, which is an essential protein for maintaining muscle integrity. The lack of dystrophin plays a pathophysiological role in the development of dilated cardiomyopathy in Duchenne muscular dystrophy. Currently, no consensus exists on specific pharmacological therapy guidelines for these patients; however, it centers around the guidelines for heart failure management. This systematic review investigated 12 randomized control trials dating back to 2005 in the pharmacotherapy of patients with dilated cardiomyopathy Duchenne muscular dystrophy. This review specifically included angiotensin-converting enzyme inhibitors, aldosterone receptor blockers, angiotensin receptor/neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Despite their limitations, these studies have shown promising effects in improving the overall heart function and prognosis in patients with this condition. However, to attain higher statistical significance, future studies should investigate larger populations and for longer periods.
Topics: Humans; Cardiomyopathy, Dilated; Muscular Dystrophy, Duchenne; Dystrophin; Angiotensin-Converting Enzyme Inhibitors; Adrenergic beta-Antagonists
PubMed: 37406964
DOI: 10.1016/j.hjc.2023.06.007 -
Neurotherapeutics : the Journal of the... Oct 2018Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in... (Review)
Review
Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety.
Topics: Animals; Dystrophin; Humans; Muscular Dystrophy, Duchenne
PubMed: 30414046
DOI: 10.1007/s13311-018-00687-z -
Trends in Molecular Medicine Jun 2016Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to... (Review)
Review
Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD.
Topics: Animals; Cell Polarity; Cell Proliferation; Dystrophin; Genetic Therapy; Humans; Mice; Mice, Inbred mdx; Muscle Development; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Satellite Cells, Skeletal Muscle
PubMed: 27161598
DOI: 10.1016/j.molmed.2016.04.002 -
Journal of Neuromuscular Diseases 2021Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for...
Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for Duchenne Muscular Dystrophy (DMD). However, these treatments have only demonstrated variable and largely sub-therapeutic levels of restored dystrophin protein in DMD patients, limiting their clinical impact. To better understand variable protein expression and the behavior of truncated dystrophin protein in vivo, we assessed turnover dynamics of restored dystrophin and dystrophin glycoprotein complex (DGC) proteins in mdx mice after exon skipping therapy, compared to those dynamics in wild type mice, using a targeted, highly-reproducible and sensitive, in vivo stable isotope labeling mass spectrometry approach in multiple muscle tissues. Through statistical modeling, we found that restored dystrophin protein exhibited altered stability and slower turnover in treated mdx muscle compared with that in wild type muscle (∼44 d vs. ∼24 d, respectively). Assessment of mRNA transcript stability (quantitative real-time PCR, droplet digital PCR) and dystrophin protein expression (capillary gel electrophoresis, immunofluorescence) support our dystrophin protein turnover measurements and modeling. Further, we assessed pathology-induced muscle fiber turnover through bromodeoxyuridine (BrdU) labeling to model dystrophin and DGC protein turnover in the context of persistent fiber degeneration. Our findings reveal sequestration of restored dystrophin protein after exon skipping therapy in mdx muscle leading to a significant extension of its half-life compared to the dynamics of full-length dystrophin in normal muscle. In contrast, DGC proteins show constant turnover attributable to myofiber degeneration and dysregulation of the extracellular matrix (ECM) in dystrophic muscle. Based on our results, we demonstrate the use of targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of disease and propose its use to optimize alternative gene correction strategies in development for DMD.
Topics: Animals; Dystroglycans; Dystrophin; Exons; Genetic Therapy; Mice; Mice, Inbred mdx; Muscle Fibers, Skeletal; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense
PubMed: 34569969
DOI: 10.3233/JND-210696 -
Molecular Therapy : the Journal of the... May 2017Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation... (Review)
Review
Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups.
Topics: Animals; Dependovirus; Dogs; Dystrophin; Genetic Therapy; Genetic Vectors; History, 20th Century; History, 21st Century; Humans; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Mutation; Protein Domains
PubMed: 28416280
DOI: 10.1016/j.ymthe.2017.02.019 -
Endokrynologia Polska 2021It is well established that thyroid hormones significantly affect skeletal muscle function, causing symptoms like myalgia and muscle weakness. Hypothyroid patients...
INTRODUCTION
It is well established that thyroid hormones significantly affect skeletal muscle function, causing symptoms like myalgia and muscle weakness. Hypothyroid patients present increased levels of creatine kinase (CK), indicating muscle destruction. Lately, we proposed new serum markers of muscle disturbances in thyroid disorders: titin (TTN) and dystrophin (DMD). The aim of this study is to determine the association between thyroid status, muscle metabolism, and serum levels of TTN and DMD in patients affected by hypoand hyperthyroidism, before and after the treatment.
MATERIAL AND METHODS
In the study 56 subjects were enrolled. The studied group consisted of 16 patients with newly diagnosed overt hypothyroidism and 20 patients with hyperthyroidism. Twenty healthy controls were also included in the study. Body composition, thyroid hormones, and biochemical markers of muscle deterioration levels were evaluated before and after restoration of euthyroidism.
RESULTS
Dystrophin and TTN levels were noticeably lower in the hypothyroid group and hyperthyroid group in comparison with controls, at the border of statistical significance. Along with the thyroid hormones and CK normalisation, DMD levels increased in the hypothyroid group, with no significant lowering of TTN levels. However, TTN concentrations and the fT3/fT4 ratio became significantly lower than in controls. Hyperthyroid patients experienced no significant changes in TTN and DMD.
CONCLUSIONS
The presented data indicate that TTN and DMD are potential new markers of musculoskeletal deterioration in thyroid disorders. In addition, the shift in TTN and DMD serum concentrations after the treatment of hypothyroidism accompanied by decreased fT3/fT4 ratio suggest the influence of the chosen therapeutic approach on muscle metabolism.
Topics: Adult; Case-Control Studies; Connectin; Dystrophin; Female; Humans; Hyperthyroidism; Male; Middle Aged; Poland; Thyroid Diseases; Thyroid Gland; Thyroid Hormones
PubMed: 33295636
DOI: 10.5603/EP.a2020.0083 -
International Journal of Molecular... Jun 2024Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from...
Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin-glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein-protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research.
Topics: Animals; Humans; Mice; Dystrophin; Integrins; Membrane Proteins; Muscular Dystrophy, Duchenne; Translational Research, Biomedical
PubMed: 38892308
DOI: 10.3390/ijms25116121 -
Medicine and Science in Sports and... Jan 2022The ability of skeletal muscle to adapt to eccentric (ECC) contraction-induced injury is known as the repeated bout effect (RBE). Despite the RBE being a...
PURPOSE
The ability of skeletal muscle to adapt to eccentric (ECC) contraction-induced injury is known as the repeated bout effect (RBE). Despite the RBE being a well-established phenomenon observed in skeletal muscle, cellular and molecular events particularly those at the membranes that contribute to the adaptive potential of muscle have yet to be established. Therefore, the purpose of this study was to examine how membrane-associated proteins respond to the RBE.
METHODS
Anterior crural muscles of C57BL/6 female mice (3-5 months) were subjected to repeated bouts of in vivo ECCs, with isometric torque being measured immediately before and after injury. A total of six bouts were completed with 7 d between each bout. Protein content of dystrophin, β-sarcoglycan, and junctophilin were then assessed via immunoblotting in injured and uninjured muscles.
RESULTS
When expressed relative to preinjury isometric torque of bout 1, deficits in postinjury isometric torque during bout 2 (38%) did not differ from bout 1 (36%; P = 0.646) and were attenuated during bouts 3 through 6 (range, 24%-15%; P ≤ 0.014). Contents of dystrophin, β-sarcoglycan, and junctophilin did not change immediately after a single bout of 50 maximal ECCs (P ≥ 0.155); however, as a result of repeated bouts, contents of dystrophin, β-sarcoglycan, and junctophilin all increased compared with muscles that completed one or no bouts of ECC contractions (P ≤ 0.003).
CONCLUSIONS
The RBE represents a physiological measure of skeletal muscle plasticity. Here, we demonstrate that repeated bouts of ECC contractions increase contents of dystrophin, β-sarcoglycan, and junctophilin and attenuate postinjury torque deficits. Given our results, accumulation of membrane-associated proteins likely contributes to strength adaptations observed after repeated bouts of ECC contractions.
Topics: Adaptation, Physiological; Animals; Dystrophin; Female; Membrane Proteins; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Skeletal; Sarcoglycans; Up-Regulation
PubMed: 34334717
DOI: 10.1249/MSS.0000000000002762 -
Proceedings of the National Academy of... Jul 2023Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the gene, leading to complete absence of dystrophin and progressive degeneration of...
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of exon 52 (Δ52), expression of an internally shortened dystrophin can be achieved by skipping of exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated Δ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). Δ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in Δ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of Δ51-52 pigs and its absence in Δ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in Δ52 vs. wild-type (WT) samples, was normalized in Δ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in Δ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in Δ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of exon 51 in Δ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of Δ51-52 pigs will show if they develop symptoms of the milder BMD.
Topics: Animals; Swine; Muscular Dystrophy, Duchenne; Dystrophin; Proteome; Stroke Volume; Ventricular Function, Left; Muscle, Skeletal; Exons
PubMed: 37428903
DOI: 10.1073/pnas.2301250120 -
Journal of Biosciences 2023Duchenne muscular dystrophy (DMD) is an X-linked genetic disease primarily affecting boys causing loss of the dystrophin protein, ultimately leading to muscle wastage... (Review)
Review
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease primarily affecting boys causing loss of the dystrophin protein, ultimately leading to muscle wastage and death by cardiac or respiratory failure. The genetic mutation involved can be overcome with antisense oligonucleotides which bind to a pre-mRNA and results in reading frame restoration by exon skipping. Phosphorodiamidate morpholino oligonucleotides (PMOs) are a class of antisense agents with a neutral backbone derived from RNA which can induce effective exon skipping. In this review, the evolution of PMOs in exon skipping therapy for the last two decades has been detailed with the gradual structural and functional advancements. Even though the success rate of PMObased therapy has been high with four FDA approved drugs, several key challenges are yet to overcome, one being the dystrophin restoration in cardiac muscle. The current scenario in further improvement of PMOs has been discussed along with the future perspectives that have the potential to revolutionize the therapeutic benefits in DMD.
Topics: Male; Humans; Morpholinos; Dystrophin; Muscular Dystrophy, Duchenne; Oligonucleotides, Antisense; Exons
PubMed: 37846020
DOI: No ID Found