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Journal articles on the topic 'Muscular dystrophy'
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1
Straub, Volker, Jill A. Rafael, Jeffrey S. Chamberlain, and Kevin P. Campbell. "Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption." Journal of Cell Biology 139, no. 2 (October 20, 1997): 375–85. http://dx.doi.org/10.1083/jcb.139.2.375.
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Genetic defects in a number of components of the dystrophin–glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin α2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.
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Ibrahim Sory, P., T. Sidi, L. Guida, K. Boureima, M. Alassane Bameye, T. Mohomodine Ibrahim, K. Abdoulaye, and C. Idrissa Ahmadou. "Dystrophie Musculaire de Duchenne: Aspects cliniques, biologiques et évolutifs à propos de cinq cas dans le service de Rhumatologie au CHU du Point G." Rhumatologie Africaine Francophone 6, no. 2 (January 19, 2024): 18–23. http://dx.doi.org/10.62455/raf.v6i2.53.
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Résumé
La dystrophie musculaire de Duchenne (DMD) due à la non expression de la dystrophine est liée au chromosome X. Décrite au 19e siècle, est la plus courante dystrophie musculaire de l’enfant [1, 2]. L’incidence est estimée à 30 cas pour 100 000 naissances [1, 2].
But- étudier les caractères cliniques, biologiques et évolutifs de la dystrophie musculaire de Duchenne.
Patients et Méthodes :
Il s’est agi d’une étude rétrospective portant sur 5 dossiers de DMD, colligés en 7 ans.
Résultats
Nous rapportons cinq dossiers de garçons colligés entre 2005 et 2012,
2012, d’âge moyen de 7 ans avec des extrêmes de 1 et 12 ans. L’hypertrophie des mollets et la présence d’un signe de Gowers chez 4/5 patients. Le caractère familial était présent chez 2 garçons âgés de 5 et 10 ans à l’inclusion dont un mariage consanguin. L’examen anatomopathologique musculaire a conclu à des lésions dystrophiques. L’immunohistochimie n’a pas trouvé d’expression de la dystrophine. La corticothérapie précocement instituée à 0,5 mg/kg/jour associée à la rééducation kinésithérapie a maintenu l’autonomie des patients.
Conclusion
La corticothérapie retarderait les complications cardio-pulmonaires. Associée à la rééducation kinésithérapie et aux conseils pratiques elle a diminué les chutes.
Mots clés : Dystrophie – Musculaire – Duchenne, Rhumatologie Bamako
Abstract:
Introduction Duchenne’s muscular dystrophy (DMD) caused by no dystrophin expression is linked to X chromosome. Described in the 19th century, it is the most common muscular dystrophy of the child [1, 2]. The incidence is estimated at 30 cases per 100 000 births [1, 2]. Goal - Study clinical, biological and evolutive aspects of the Duchenne's Muscular Dystrophy.
Patients and Methods:
It was a retrospective study about 5 cases of DMD, collected in 7 years [2005-2012].
Results During our study from the period of 2005 to 2012, we had 5 cases of boys with an average age of 7 years and the extreme age from 1 year to 12 years. The calf’s hypertrophy and the presence of a Gowers’s sign in 4/5 patients. Family caracteristic was present in two boys aged 5 and 10 years with a consanguineous marriage. Muscular Histological examination concluded dystrophic lesions. The immunohistiochemistry found no expression of dystrophin. Corticosteroids early established at 0.5 mg / kg / day combined with physiotherapy rehabilitation maintained the autonomy of patients. .
Conclusion Corticosteroids would slow douwn cardiopulmonary complications. Associated with the physiotherapy rehabilitation and practical advice, it has decreased falls.
Keywords: Duchenne’s muscular dystrophy, Rheumatology, Bamako
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Steen, Michelle S., Marvin E. Adams, Yan Tesch, and Stanley C. Froehner. "Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1." Molecular Biology of the Cell 20, no. 1 (January 2009): 146–52. http://dx.doi.org/10.1091/mbc.e08-08-0811.
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Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.
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Spiro, Alfred J. "Muscular Dystrophy." Pediatrics In Review 16, no. 11 (November 1, 1995): 437. http://dx.doi.org/10.1542/pir.16.11.437.
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Several varieties of muscular dystrophy can be distinguished on clinical, genetic, morphologic, and physiologic grounds. The classification includes Duchenne and Becker muscular dystrophies, both X-linked disorders; facioscapulohumeral muscular dystrophy, which is autosomal dominant; and limb-girdle muscular dystrophy, generally autosomal recessive. Duchenne muscular dystrophy (DMD), which occurs in approximately 1 in 3500 live male births, has no recognizable signs or symptoms at birth. However, markedly elevated serum creatine kinase always is demonstrable, even at birth. A molecular diagnosis can be made at any time in the patient's lifetime by demonstrating the defect in the dystrophin gene, the absence of dystrophin in a muscle biopsy, and the characteristic morphologic abnormalities.
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Sitzia, Clementina, Andrea Farini, Federica Colleoni, Francesco Fortunato, Paola Razini, Silvia Erratico, Alessandro Tavelli, et al. "Improvement of Endurance of DMD Animal Model Using Natural Polyphenols." BioMed Research International 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/680615.
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Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-κB deactivation, and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in terms of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascularization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to coadjuvate the treatment of DMD.
6
Teramoto, Naomi, Hidetoshi Sugihara, Keitaro Yamanouchi, Katsuyuki Nakamura, Koichi Kimura, Tomoko Okano, Takanori Shiga, et al. "Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy." Disease Models & Mechanisms 13, no. 9 (August 28, 2020): dmm044701. http://dx.doi.org/10.1242/dmm.044701.
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ABSTRACTDystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.
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Bergman, Robert L., Karen D. Inzana, William E. Monroe, Linda G. Shell, Ling A. Liu, Eva Engvall, and G. Diane Shelton. "Dystrophin-Deficient Muscular Dystrophy in a Labrador Retriever." Journal of the American Animal Hospital Association 38, no. 3 (May 1, 2002): 255–61. http://dx.doi.org/10.5326/0380255.
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Sex-linked muscular dystrophy associated with dystrophin deficiency has been reported in several breeds of dogs and is best characterized in the golden retriever. In this case report, a young, male Labrador retriever with dystrophin-deficient muscular dystrophy is presented. Clinical signs included generalized weakness, lingual hypertrophy, and dysphagia. Electromyographic abnormalities including complex repetitive discharges were present. Serum creatine kinase concentration was dramatically elevated. Histopathological changes within a muscle biopsy specimen confirmed a dystrophic myopathy, and dystrophin deficiency was demonstrated by immunohisto-chemical staining. While X-linked muscular dystrophy has not previously been reported in the Labrador retriever, a hereditary myopathy with an autosomal recessive mode of inheritance has been characterized. A correct diagnosis and classification of these two disorders are critical for breeders and owners since both the mode of inheritance and the prognosis differ.
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Gambino, Anya N., Pamela J. Mouser, G. Diane Shelton, and Nena J. Winand. "Emergent Presentation of a Cat with Dystrophin-Deficient Muscular Dystrophy." Journal of the American Animal Hospital Association 50, no. 2 (March 1, 2014): 130–35. http://dx.doi.org/10.5326/jaaha-ms-5973.
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This report describes a case of feline dystrophin-deficient muscular dystrophy (DDMD) with an atypical clinical presentation. A novel gene mutation is reported to be responsible for dystrophin-deficient hypertrophic muscular dystrophy. In an emergency setting, clinicians should be aware of muscular dystrophy in young cats and the importance of elevated creatine kinase (CK) activity. Muscular dystrophy is rare but can present both a diagnostic and therapeutic challenge in an emergency setting. Patients with muscular dystrophy have a progressive disease with no specific treatment and have an increased risk for death during their hospital stay.
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Baraibar-Churio, Arantxa, Míriam Bobadilla, Florencio J. D. Machado, Neira Sáinz, Carmen Roncal, Gloria Abizanda, Felipe Prósper, Josune Orbe, and Ana Pérez-Ruiz. "Deficiency of MMP-10 Aggravates the Diseased Phenotype of Aged Dystrophic Mice." Life 11, no. 12 (December 14, 2021): 1398. http://dx.doi.org/10.3390/life11121398.
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Matrix metalloproteinases (MMPs) have been implicated in the progression of muscular dystrophy, and recent studies have reported the role of MMP-10 in skeletal muscle pathology of young dystrophic mice. Nevertheless, its involvement in dystrophin-deficient hearts remains unexplored. Here, we aimed to investigate the involvement of MMP-10 in the progression of severe muscular dystrophy and to characterize MMP-10 loss in skeletal and cardiac muscles of aged dystrophic mice. We examined the histopathological effect of MMP-10 ablation in aged mdx mice, both in the hind limb muscles and heart tissues. We found that MMP-10 loss compromises survival rates of aged mdx mice, with skeletal and cardiac muscles developing a chronic inflammatory response. Our findings indicate that MMP-10 is implicated in severe muscular dystrophy progression, thus identifying a new area of research that could lead to future therapies for dystrophic muscles.
10
Bandikatla, Sarada. "Muscular Dystrophy – Review." International Journal of Psychosocial Rehabilitation 24, no. 4 (April 30, 2020): 6540–48. http://dx.doi.org/10.37200/ijpr/v24i4/pr2020464.
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Dosani, Minaj, and Harish Kumar Singhal. "An Ayurvedic Approach in Muscular Dystrophy in Children." International Journal of Health Sciences and Research 14, no. 3 (March 9, 2024): 105–16. http://dx.doi.org/10.52403/ijhsr.20240318.
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Duchenne muscular dystrophy stands out as the most prevalent and severe form of childhood muscular dystrophy, impacting approximately one in every 5200 male births. It results from dystrophin deficiency, a condition inherited through X-linked recessive traits due to a missing or altered dystrophin protein encoded by the DMD gene located on chromosome Xp21. Unfortunately, this myopathy is currently incurable, often leading to mortality between the ages of 20-25. The primary pharmaceutical intervention for Duchenne muscular dystrophy involves corticosteroids, though they come with long-term negative consequences.In the realm of Ayurveda, Duchenne muscular dystrophy falls under the classification of Medomamsa dushti, attributed to Vata doshas and stemming from Bheejabagahaavyava dushti. Ayurvedic strategies for management emphasize the promotion of regeneration in neuromuscular illnesses, employing a combination of Ayurvedic oral drugs and Panchakarma therapies. Key words: DMD, Dystrophin, Muscular Dystrophy, Medovaha Srotodushti
12
Spaulding, HR, C. Ballmann, JC Quindry, MB Hudson, and JT Selsby. "Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models." JRSM Cardiovascular Disease 8 (January 2019): 204800401987958. http://dx.doi.org/10.1177/2048004019879581.
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Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.
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Pelosi, Laura, Laura Forcina, Carmine Nicoletti, Bianca Maria Scicchitano, and Antonio Musarò. "Increased Circulating Levels of Interleukin-6 Induce Perturbation in Redox-Regulated Signaling Cascades in Muscle of Dystrophic Mice." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1987218.
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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.
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Srivastava, Niraj Kumar, Somnath Mukherjee, and Vijay Nath Mishra. "Metabolic Disturbance in Patients with Muscular Dystrophy and Reflection of Altered Enzyme Activity in Dystrophic Muscle: One Critical View." Journal of Biomedical Research & Environmental Sciences 1, no. 8 (December 2020): 393–403. http://dx.doi.org/10.37871/jbres1171.
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Muscular dystrophies are inherited myogenic diseases and considered by progressive muscle wasting and weakness with variable distribution and severity. The essential characteristics of muscular dystrophies are selective involvement, significant wasting and weakness of muscles. The most common and frequent types of muscular dystrophies are Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Facioscapulohumeral Dystrophy (FSHD) and Limb Girdle Muscular Dystrophy (LGMD). Metabolic disturbance is observed in muscular dystrophy patients (DMD, BMD, FSHD and LGMD-2B). Alteration in the level of metabolites (BCAA, Glu/ Gln, Ace, alanine, glucose, histidine, propionate, tyrosine and fumarate) in dystrophic muscle reflects the alteration in the activity of enzymes. Collectively, these observations propose that there is alteration in the rate of glycolysis, TCA cycle, fatty acid oxidation, gluconeogenesis pathway and protein metabolism (catabolism & anabolism) in the muscular dystrophy patients. Metabolic disturbance, further provide the explanation about the pathophysiology of muscular dystrophy.
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Watchko, Jon F., Terrence L. O'Day, and Eric P. Hoffman. "Functional characteristics of dystrophic skeletal muscle: insights from animal models." Journal of Applied Physiology 93, no. 2 (August 1, 2002): 407–17. http://dx.doi.org/10.1152/japplphysiol.01242.2001.
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Muscular dystrophies are a clinically and genetically heterogeneous group of disorders that show myofiber degeneration and regeneration. Identification of animal models of muscular dystrophy has been instrumental in research on the pathogenesis, pathophysiology, and treatment of these disorders. We review our understanding of the functional status of dystrophic skeletal muscle from selected animal models with a focus on 1) the mdx mouse model of Duchenne muscular dystrophy, 2) the Bio 14.6 δ-sarcoglycan-deficient hamster model of limb-girdle muscular dystrophy, and 3) transgenic null mutant murine lines of sarcoglycan (α, β, δ, and γ) deficiencies. Although biochemical data from these models suggest that the dystrophin-sarcoglycan-dystroglycan-laminin network is critical for structural integrity of the myofiber plasma membrane, emerging studies of muscle physiology suggest a more complex picture, with specific functional deficits varying considerably from muscle to muscle and model to model. It is likely that changes in muscle structure and function, downstream of the specific, primary biochemical deficiency, may alter muscle contractile properties.
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Hoffman, Eric P. "Muscular Dystrophy." Archives of Pathology & Laboratory Medicine 123, no. 11 (November 1, 1999): 1050–52. http://dx.doi.org/10.5858/1999-123-1050-md.
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Abstract The application of cloned genes and their protein products to molecular diagnostics has been an increasingly important area of pathology. The first gene to be identified by positional cloning was the Duchenne muscular dystrophy gene, mutations of which cause one of the most common and most devastating human inherited conditions. The identification of the responsible gene and the encoded dystrophin protein has resulted in a large series of studies concerning the other components of the membrane cytoskeleton of myofibers and their involvement in different forms of muscular dystrophy. Through the study of patients deficient in specific components of the muscle fiber, much is being learned about normal myofiber structure and function and dysfunction in disease states. A new frontier is the application of the normal genes and proteins toward patient therapeutics (gene therapy). Although highly experimental, delivery of therapeutic genes promises to become an important medical practice.
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Nogami, Ken'ichiro, Yusuke Maruyama, Fusako Sakai-Takemura, Norio Motohashi, Ahmed Elhussieny, Michihiro Imamura, Satoshi Miyashita, et al. "Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice." Human Molecular Genetics 30, no. 11 (April 5, 2021): 1006–19. http://dx.doi.org/10.1093/hmg/ddab100.
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Abstract Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.
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Hoang, Tiffany, and Regina A. E. Dowdy. "A Review of Muscular Dystrophies." Anesthesia Progress 71, no. 1 (March 2024): 44–52. http://dx.doi.org/10.2344/673191.
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Muscular dystrophy encompasses a group of genetic conditions with progressive muscle damage and weakness. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders that affect the production of the protein dystrophin. Emery-Dreifuss muscular dystrophy (EDMD) is typically an X-linked-recessive disorder involving the gene that codes for emerin. Facioscapulohumeral muscular dystrophy and oculopharyngeal muscular dystrophy (OPMD) are both autosomal dominant disorders. Although commonly mistaken as a condition in which patients are susceptible to malignant hyperthermia with volatile inhalational anesthetics, muscular dystrophy is more closely associated with rhabdomyolysis. Providers developing an anesthetic plan for dental patients with muscular dystrophy must take into consideration the patient’s baseline cardiac and pulmonary function as well as the potential for abnormalities. Nondepolarizing neuromuscular blocker use is safe but likely to result in prolonged skeletal muscle relaxation. Succinylcholine and volatile anesthetics are generally contraindicated due to the risks of rhabdomyolysis and hyperkalemia with subsequent ventricular fibrillation, cardiac arrest, and death if left untreated. In-depth understanding of the more commonly encountered forms of muscular dystrophy is vital to providing safe and effective ambulatory anesthesia care for patients undergoing dental treatment outside the traditional hospital operating room setting.
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Peter, Angela K., Jamie L. Marshall, and Rachelle H. Crosbie. "Sarcospan reduces dystrophic pathology: stabilization of the utrophin–glycoprotein complex." Journal of Cell Biology 183, no. 3 (November 3, 2008): 419–27. http://dx.doi.org/10.1083/jcb.200808027.
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Mutations in the dystrophin gene cause Duchenne muscular dystrophy and result in the loss of dystrophin and the entire dystrophin–glycoprotein complex (DGC) from the sarcolemma. We show that sarcospan (SSPN), a unique tetraspanin-like component of the DGC, ameliorates muscular dystrophy in dystrophin-deficient mdx mice. SSPN stabilizes the sarcolemma by increasing levels of the utrophin–glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. SSPN directly interacts with the UGC and functions to stabilize utrophin protein without increasing utrophin transcription. These findings reveal the importance of protein stability in the prevention of muscular dystrophy and may impact the future design of therapeutics for muscular dystrophies.
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Carberry, Steven, Margit Zweyer, Dieter Swandulla, and Kay Ohlendieck. "Profiling of Age-Related Changes in theTibialis AnteriorMuscle Proteome of the mdx Mouse Model of Dystrophinopathy." Journal of Biomedicine and Biotechnology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/691641.
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X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdxtibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdxtibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.
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Blake, Derek J., Andrew Weir, Sarah E. Newey, and Kay E. Davies. "Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle." Physiological Reviews 82, no. 2 (April 1, 2002): 291–329. http://dx.doi.org/10.1152/physrev.00028.2001.
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The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.
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González-Jamett, Arlek, Walter Vásquez, Gabriela Cifuentes-Riveros, Rafaela Martínez-Pando, Juan C. Sáez, and Ana M. Cárdenas. "Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies." Biomedicines 10, no. 2 (February 21, 2022): 507. http://dx.doi.org/10.3390/biomedicines10020507.
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Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.
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Niranjan, Nandita, Satvik Mareedu, Yimin Tian, Kasun Kodippili, Nadezhda Fefelova, Antanina Voit, Lai-Hua Xie, Dongsheng Duan, and Gopal J. Babu. "Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy." American Journal of Physiology-Cell Physiology 317, no. 4 (October 1, 2019): C813—C824. http://dx.doi.org/10.1152/ajpcell.00146.2019.
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Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C2C12 resulted in decreased SERCA pump activity, reduced SR Ca2+ load, and increased intracellular Ca2+ ([Formula: see text]) concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective [Formula: see text] cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the [Formula: see text] mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the [Formula: see text] cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.
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Niebrój-Dobosz, Irena, and Irena Hausmanowa-Petrusewicz. "The involvement of oxidative stress in determining the severity and progress of pathological processes in dystrophin-deficient muscles." Acta Biochimica Polonica 52, no. 2 (May 25, 2005): 449–52. http://dx.doi.org/10.18388/abp.2005_3458.
Full textAbstract:
In both forms of muscular dystrophy, the severe Duchenne's muscular dystrophy (DMD) with lifespan shortened to about 20 years and the milder Becker dystrophy (BDM) with normal lifespan, the gene defect is located at chromosome locus Xp21. The location is the same in the experimental model of DMD in the mdx mice. As the result of the gene defect a protein called dystrophin is either not synthesized, or is produced in traces. Although the structure of this protein is rather well established there are still many controversies about the dystrophin function. The most accepted suggestion supposes that it stabilizes sarcolemma in the course of the contraction-relaxation cycle. Solving the problem of dystrophin function is a prerequisite for introduction of an effective therapy. Among the different factors which might be responsible for the appearance and progress of dystrophic changes in muscles there is an excessive action of oxidative stress. In this review data indicating the influence of oxidative stress on the severity of the pathologic processes in dystrophy are discussed. Several pieces of data indicating the action of oxidative damage to different macromolecules in DMD/BDM are presented. Special attention is devoted to the degree of oxidative damage to muscle proteins, the activity of neuronal nitric oxide synthase (nNOS) and their involvement in defining the severity of the dystrophic processes. It is indicated that the severity of the morbid process is related to the degree of oxidative damage to muscle proteins and the decrease of the nNOS activity in muscles. Estimation of the degree of the destructive action of oxidative stress in muscular dystrophy may be a useful marker facilitating introduction of an effective antioxidant therapy and regulation of nNOS activity.
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lordlin, Dr R. T. J. R. Lordlin, and Dr Franklin Shaju. "PHYSIO IN DUCHENNE MUSCULAR DYSTROPHY (DMD)." IDC International Journal 8, no. 4 (October 10, 2021): 1–4. http://dx.doi.org/10.47211/idcij.2021.v08i04.001.
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Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy and is caused by mutations in the dystrophin gene. Dystrophin, together with several other protein components, is part of a complex known as the dystrophin glycoprotein complex (DGC). The DGC plays an essential role in maintaining the structural integrity of the muscle cell membrane by providing a link between the extracellular matrix and the cytoskeleton
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Hilton, Stephanie, Matthias Christen, Thomas Bilzer, Vidhya Jagannathan, Tosso Leeb, and Urs Giger. "Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy." International Journal of Molecular Sciences 24, no. 4 (February 6, 2023): 3192. http://dx.doi.org/10.3390/ijms24043192.
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Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.
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Gumerson, Jessica D., and Daniel E. Michele. "The Dystrophin-Glycoprotein Complex in the Prevention of Muscle Damage." Journal of Biomedicine and Biotechnology 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/210797.
Full textAbstract:
Muscular dystrophies are genetically diverse but share common phenotypic features of muscle weakness, degeneration, and progressive decline in muscle function. Previous work has focused on understanding how disruptions in the dystrophin-glycoprotein complex result in muscular dystrophy, supporting a hypothesis that the muscle sarcolemma is fragile and susceptible to contraction-induced injury in multiple forms of dystrophy. Although benign in healthy muscle, contractions in dystrophic muscle may contribute to a higher degree of muscle damage which eventually overwhelms muscle regeneration capacity. While increased susceptibility of muscle to mechanical injury is thought to be an important contributor to disease pathology, it is becoming clear that not all DGC-associated diseases share this supposed hallmark feature. This paper outlines experimental support for a function of the DGC in preventing muscle damage and examines the evidence that supports novel functions for this complex in muscle that when impaired, may contribute to the pathogenesis of muscular dystrophy.
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Srivastava, Pallavi, Kiran Preet Malhotra, Nuzhat Husain, Hardeep Singh Malhotra, Dinkar Kulshreshtha, and Akanksha Anand. "Diagnosing Muscular Dystrophies: Comparison of Techniques and Their Cost Effectiveness: A Multi-institutional Study." Journal of Neurosciences in Rural Practice 11, no. 03 (June 12, 2020): 420–29. http://dx.doi.org/10.1055/s-0040-1713301.
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Abstract Background The diagnosis of muscular dystrophies involves clinical discretion substantiated by dystrophic changes on muscle biopsy. The different subtypes of muscular dystrophy can be diagnosed using techniques to identify the loss of protein or molecular alterations. Materials and Methods Clinically suspicious cases confirmed to have muscular dystrophy on muscle biopsy seen at two tertiary care centers in North India were enrolled for the study. Immunohistochemistry (IHC) for dystrophin, merosin, sarcoglycan, emerin, and dysferlin proteins was performed. The spectrum of muscular dystrophies diagnosed was analyzed. Cost of diagnosing the cases using IHC was estimated and compared with that of standard molecular tests available for the diagnosis of muscular dystrophies. Statistics Descriptive statistics were used for data analysis. Mean and standard deviations were used for continuous variables, whereas categorical variables were analyzed using frequency percentage. Results A total of 47 cases of muscular dystrophies were studied. This included nine cases of Duchenne, three cases of Becker’s dystrophy, and one dystrophinopathy carrier. One case of α, seven cases of β, and two cases of δ sarcoglycanopathy, along with two cases of facioscapulohumeral dystrophy and a single case of dysferlinopathy were detected. Genetic studies were required for a subset of 16 cases. The cost of using muscle biopsy and IHC was substantially lower than that of molecular methods for the identification of muscular dystrophy subtypes. Conclusion We detailed an algorithmic approach for diagnosing muscular dystrophies using muscle biopsy. The prevalence of biopsy proven muscular dystrophies from two tertiary care centers in North India is compared with that from other centers. Genetic studies are currently of limited availability in India and are more expensive as compared with biopsy and IHC. Using these methodologies sequentially with a “biopsy first approach” may be the prudent approach for low-income countries.
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Gargan, Stephen, Paul Dowling, Margit Zweyer, Michael Henry, Paula Meleady, Dieter Swandulla, and Kay Ohlendieck. "Proteomic Identification of Markers of Membrane Repair, Regeneration and Fibrosis in the Aged and Dystrophic Diaphragm." Life 12, no. 11 (October 22, 2022): 1679. http://dx.doi.org/10.3390/life12111679.
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Deficiency in the membrane cytoskeletal protein dystrophin is the underlying cause of the progressive muscle wasting disease named Duchenne muscular dystrophy. In order to detect novel disease marker candidates and confirm the complexity of the pathobiochemical signature of dystrophinopathy, mass spectrometric screening approaches represent ideal tools for comprehensive biomarker discovery studies. In this report, we describe the comparative proteomic analysis of young versus aged diaphragm muscles from wild type versus the dystrophic mdx-4cv mouse model of X-linked muscular dystrophy. The survey confirmed the drastic reduction of the dystrophin-glycoprotein complex in the mdx-4cv diaphragm muscle and concomitant age-dependent changes in key markers of muscular dystrophy, including proteins involved in cytoskeletal organization, metabolite transportation, the cellular stress response and excitation-contraction coupling. Importantly, proteomic markers of the regulation of membrane repair, tissue regeneration and reactive myofibrosis were detected by mass spectrometry and changes in key proteins were confirmed by immunoblotting. Potential disease marker candidates include various isoforms of annexin, the matricellular protein periostin and a large number of collagens. Alterations in these proteoforms can be useful to evaluate adaptive, compensatory and pathobiochemical changes in the intracellular cytoskeleton, myofiber membrane integrity and the extracellular matrix in dystrophin-deficient skeletal muscle tissues.
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Chen, Yi-Wen, Po Zhao, Rehannah Borup, and Eric P. Hoffman. "Expression Profiling in the Muscular Dystrophies." Journal of Cell Biology 151, no. 6 (December 11, 2000): 1321–36. http://dx.doi.org/10.1083/jcb.151.6.1321.
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We used expression profiling to define the pathophysiological cascades involved in the progression of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and α-sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative comparisons of duplicate datasets. We found evidence for both incomplete differentiation of patient muscle, and for dedifferentiation of myofibers to alternative lineages with advancing age. One developmentally regulated gene characterized in detail, α-cardiac actin, showed abnormal persistent expression after birth in 60% of Duchenne dystrophy myofibers. The majority of myofibers (∼80%) remained strongly positive for this protein throughout the course of the disease. Other developmentally regulated genes that showed widespread overexpression in these muscular dystrophies included embryonic myosin heavy chain, versican, acetylcholine receptor α-1, secreted protein, acidic and rich in cysteine/osteonectin, and thrombospondin 4. We hypothesize that the abnormal Ca2+ influx in dystrophin- and α-sarcoglycan–deficient myofibers leads to altered developmental programming of developing and regenerating myofibers. The finding of upregulation of HLA-DR and factor XIIIa led to the novel identification of activated dendritic cell infiltration in dystrophic muscle; these cells mediate immune responses and likely induce microenvironmental changes in muscle. We also document a general metabolic crisis in dystrophic muscle, with large scale downregulation of nuclear-encoded mitochondrial gene expression. Finally, our expression profiling results show that primary genetic defects can be identified by a reduction in the corresponding RNA.
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Faqih, M. Izza Zulfana, Wahyu Tri Sudaryanto, and Salma Muazzaroh. "ACTIVE ASSISTED MOVEMENT DALAM MENJAGA KEMAMPUAN FUNGSIONAL PADA KONDISI DUCHENNE MUSCULAR DYSTROPHY." Journal of Innovation Research and Knowledge 3, no. 1 (July 1, 2023): 5047–52. http://dx.doi.org/10.53625/jirk.v3i1.5990.
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Background: Duchenne muscular dystrophy which is a recessive x-linked disorder that often affects males. Duchenne muscular dystrophy is caused by mutations in the dystrophin gene at the Xp21 locus so that dystrophin protein is not produced or dystrophin deficiency and structural abnormalities occur. Dystrophinopathies are X-linked recessive disorders affecting 1 in 5,000 to 1 in 6,000 live male births. The prevalence of DMD is less than 10 cases per 100,000 males. Objective: Physiotherapy management in this case aims to determine the benefits of providing physiotherapy interventions in the form of active assisted and passive movement and stretching in patients with Duchenne muscular dystrophy. Methods: This case report was conducted at PLDPI Surakarta by taking patients with Duchenne muscular dystrophy cases by providing physiotherapy modalities in the form of active assisted and passive movement and stretching for 3 physiotherapy sessions. Furthermore, measurements were taken with the GMFM and XOTR Scale in the first to third physiotherapy. Results: From the physiotherapy management given, it was found that functional ability and muscle strength remained unchanged and did not develop. Conclusion: Physiotherapy management in this case report is proven to be able to maintain functional ability and muscle strength in patients with Duchenne muscular dystrophy.
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Jufan, Akhmad Yun, Djayanti Sari, and Karlina Mahardieni. "DUCHENNE MUSCULER DYSTROPHY." Jurnal Komplikasi Anestesi 3, no. 2 (May 27, 2023): 47–53. http://dx.doi.org/10.22146/jka.v3i2.7242.
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Duchenne muscular dystrophy merupakan suatu kelainan otot yang sering ditemui. Penyakit ini terpaut pada kromosom X yang disebabkan oleh mutasi gen dystrophin. Gejalanya berupa kelemahan otot proksimal yang berat, bersifat degenerasi progresif dan infi ltrasi lemak ke otot. Efek duchenne muscular dystrophy terhadap otot respirasi dan berhubungan dengan kardio-miopati yang dapat mengarah ke kematian.Dilaporkan anak laki-laki usia 12 tahun dengan diagnosa duchenne muscular dystrophy dd/ Baker’s muscular dystrophy dilakukan prosedur biopsi. Pasien dinilai sebagai status fi sik ASA 2 yang dilakukan general anesthesia dengan teknik TIVA. Setelah persiapan preoperasi, pasien diberikan ko induksi dengan midazolam 1,5mg, induksi dengan ketamine 20mg. Pemeliharaan anestesi dengan O2 melalui nasal kanul. Hemodinamik durante operasi stabil dengan jalan nafas terjaga dengan kepala ekstensi. Operasiberlangsung selama 20menit. Perdarahan minimal dan urine output 25cc. Kondisi pasien setelah operasi stabil dan kembali ke bangsal.
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Danisovic, Lubos, Martina Culenova, and Maria Csobonyeiova. "Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy." Cells 7, no. 12 (December 7, 2018): 253. http://dx.doi.org/10.3390/cells7120253.
Full textAbstract:
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutation of the DMD gene which encodes the protein dystrophin. This dystrophin defect leads to the progressive degeneration of skeletal and cardiac muscles. Currently, there is no effective therapy for this disorder. However, the technology of cell reprogramming, with subsequent controlled differentiation to skeletal muscle cells or cardiomyocytes, may provide a unique tool for the study, modeling, and treatment of Duchenne muscular dystrophy. In the present review, we describe current methods of induced pluripotent stem cell generation and discuss their implications for the study, modeling, and development of cell-based therapies for Duchenne muscular dystrophy.
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Iqbal, Aqsa, Ulrike May, Stuart N. Prince, Tero A. H. Järvinen, and Ahlke Heydemann. "Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology." Pharmaceutics 13, no. 9 (September 18, 2021): 1506. http://dx.doi.org/10.3390/pharmaceutics13091506.
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Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.
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Beckers, Evy, Ine Cornelis, Sofie F. M. Bhatti, Pascale Smets, G. Diane Shelton, Ling T. Guo, Luc Peelman, and Bart J. G. Broeckx. "A Nonsense Variant in the DMD Gene Causes X-Linked Muscular Dystrophy in the Maine Coon Cat." Animals 12, no. 21 (October 25, 2022): 2928. http://dx.doi.org/10.3390/ani12212928.
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(1) Feline dystrophin-deficient muscular dystrophy (ddMD) is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles and is caused by variants in the DMD gene. To date, only two feline causal variants have been identified. This study reports two cases of male Maine coon siblings that presented with muscular hypertrophy, growth retardation, weight loss, and vomiting. (2) Both cats were clinically examined and histopathology and immunofluorescent staining of the affected muscle was performed. DMD mRNA was sequenced to identify putative causal variants. (3) Both cats showed a significant increase in serum creatine kinase activity. Electromyography and histopathological examination of the muscle samples revealed abnormalities consistent with a dystrophic phenotype. Immunohistochemical testing revealed the absence of dystrophin, confirming the diagnosis of dystrophin-deficient muscular dystrophy. mRNA sequencing revealed a nonsense variant in exon 11 of the feline DMD gene, NC_058386.1 (XM_045050794.1): c.1180C>T (p.(Arg394*)), which results in the loss of the majority of the dystrophin protein. Perfect X-linked segregation of the variant was established in the pedigree. (4) ddMD was described for the first time in the Maine coon and the c.1180C>T variant was confirmed as the causal variant.
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Assereto, Stefania, Silvia Stringara, Federica Sotgia, Gloria Bonuccelli, Aldobrando Broccolini, Marina Pedemonte, Monica Traverso, et al. "Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment." American Journal of Physiology-Cell Physiology 290, no. 2 (February 2006): C577—C582. http://dx.doi.org/10.1152/ajpcell.00434.2005.
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In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, β-dystroglycan, and α-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663–1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.
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Rubi, Lena, Vaibhavkumar S. Gawali, Helmut Kubista, Hannes Todt, Karlheinz Hilber, and Xaver Koenig. "Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes." Cellular Physiology and Biochemistry 36, no. 3 (2015): 1049–58. http://dx.doi.org/10.1159/000430278.
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Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.
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D’Amario, Domenico, Aoife Gowran, Francesco Canonico, Elisa Castiglioni, Davide Rovina, Rosaria Santoro, Pietro Spinelli, et al. "Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine." Journal of Clinical Medicine 7, no. 9 (September 19, 2018): 291. http://dx.doi.org/10.3390/jcm7090291.
Full textAbstract:
Duchenne’s muscular dystrophy is an X-linked neuromuscular disease that manifests as muscle atrophy and cardiomyopathy in young boys. However, a considerable percentage of carrier females are often diagnosed with cardiomyopathy at an advanced stage. Existing therapy is not disease-specific and has limited effect, thus many patients and symptomatic carrier females prematurely die due to heart failure. Early detection is one of the major challenges that muscular dystrophy patients, carrier females, family members and, research and medical teams face in the complex course of dystrophic cardiomyopathy management. Despite the widespread adoption of advanced imaging modalities such as cardiac magnetic resonance, there is much scope for refining the diagnosis and treatment of dystrophic cardiomyopathy. This comprehensive review will focus on the pertinent clinical aspects of cardiac disease in muscular dystrophy while also providing a detailed consideration of the known and developing concepts in the pathophysiology of muscular dystrophy and forthcoming therapeutic options.
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Kikuchi, Tateki. "Caveolin-3: A Causative Process of Chicken Muscular Dystrophy." Biomolecules 10, no. 9 (August 20, 2020): 1206. http://dx.doi.org/10.3390/biom10091206.
Full textAbstract:
The etiology of chicken muscular dystrophy is the synthesis of aberrant WW domain containing E3 ubiquitin-protein ligase 1 (WWP1) protein made by a missense mutation of WWP1 gene. The β-dystroglycan that confers stability to sarcolemma was identified as a substrate of WWP protein, which induces the next molecular collapse. The aberrant WWP1 increases the ubiquitin ligase-mediated ubiquitination following severe degradation of sarcolemmal and cytoplasmic β-dystroglycan, and an erased β-dystroglycan in dystrophic αW fibers will lead to molecular imperfection of the dystrophin-glycoprotein complex (DGC). The DGC is a core protein of costamere that is an essential part of force transduction and protects the muscle fibers from contraction-induced damage. Caveolin-3 (Cav-3) and dystrophin bind competitively to the same site of β-dystroglycan, and excessive Cav-3 on sarcolemma will block the interaction of dystrophin with β-dystroglycan, which is another reason for the disruption of the DGC. It is known that fast-twitch glycolytic fibers are more sensitive and vulnerable to contraction-induced small tears than slow-twitch oxidative fibers under a variety of diseased conditions. Accordingly, the fast glycolytic αW fibers must be easy with rapid damage of sarcolemma corruption seen in chicken muscular dystrophy, but the slow oxidative fibers are able to escape from these damages.
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Arora, Shivani, and Chirag Arora. "A REVIEW ON CONCEPTUAL STUDY OF MUSCULAR DYSTROPHIES: AN AYURVEDIC PERSPECTIVE." International Journal of Research in Ayurveda and Pharmacy 13, no. 01 (February 23, 2022): 92–95. http://dx.doi.org/10.7897/2277-4343.130121.
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Muscular dystrophies (M.D.) are a category of hereditary illnesses defined by degeneration of the skeletal muscles that control mobility, culminating in muscle atrophy, weakness, confinement to a wheelchair, and eventually death. The most common muscular dystrophy is Duchenne muscular dystrophy (DMD), caused by a lack of the dystrophin gene. In Ayurvedic scriptures, muscular dystrophy is not explicitly linked to any ailment. The notion of Adibala pravritta vyadhi in Ayurveda helps to explain this aetiology. Pathogenesis occurs here due to Beejobhagavayava dushti, which leads to Mamsa Vata dushti. Because there is no specific treatment for muscle dystrophies in any medical system, the modern therapeutic approach of M.D is corticosteroids, physical therapy, respiratory assistance and gene therapy. In muscular dystrophy patients, Ayurvedic treatments such as Santarpana chikitsa, a collection of herbo-mineral medications, and specific Panchkarma therapies have an apparent protective effect and a prolonged survival rate. The current review article discusses the notion of muscular dystrophy from an Ayurvedic perspective and treatments and drugs that can help with the disease.
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Freund, Aline Andrade, Rosana Herminia Scola, Raquel Cristina Arndt, Paulo José Lorenzoni, Claudia Kamoy Kay, and Lineu Cesar Werneck. "Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach." Arquivos de Neuro-Psiquiatria 65, no. 1 (March 2007): 73–76. http://dx.doi.org/10.1590/s0004-282x2007000100016.
Full textAbstract:
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.
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Wehling, Michelle, Melissa J. Spencer, and James G. Tidball. "A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice." Journal of Cell Biology 155, no. 1 (October 1, 2001): 123–32. http://dx.doi.org/10.1083/jcb.200105110.
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Dystrophin-deficient muscles experience large reductions in expression of nitric oxide synthase (NOS), which suggests that NO deficiency may influence the dystrophic pathology. Because NO can function as an antiinflammatory and cytoprotective molecule, we propose that the loss of NOS from dystrophic muscle exacerbates muscle inflammation and fiber damage by inflammatory cells. Analysis of transgenic mdx mice that were null mutants for dystrophin, but expressed normal levels of NO in muscle, showed that the normalization of NO production caused large reductions in macrophage concentrations in the mdx muscle. Expression of the NOS transgene in mdx muscle also prevented the majority of muscle membrane injury that is detectable in vivo, and resulted in large decreases in serum creatine kinase concentrations. Furthermore, our data show that mdx muscle macrophages are cytolytic at concentrations that occur in dystrophic, NOS-deficient muscle, but are not cytolytic at concentrations that occur in dystrophic mice that express the NOS transgene in muscle. Finally, our data show that antibody depletions of macrophages from mdx mice cause significant reductions in muscle membrane injury. Together, these findings indicate that macrophages promote injury of dystrophin-deficient muscle, and the loss of normal levels of NO production by dystrophic muscle exacerbates inflammation and membrane injury in muscular dystrophy.
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Spaulding, Hannah R., Tiffany Quindry, Kayleen Hammer, John C. Quindry, and Joshua T. Selsby. "Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice." Journal of Applied Physiology 127, no. 4 (October 1, 2019): 1058–66. http://dx.doi.org/10.1152/japplphysiol.00162.2019.
Full textAbstract:
Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As quercetin activates PGC-1α through Sirtuin-1, an NAD+-dependent deacetylase, the depleted NAD+ in dystrophic skeletal muscle may limit quercetin efficacy; hence, supplementation with the NAD+ donor, nicotinamide riboside (NR), may facilitate quercetin efficacy. Lisinopril (Lis) protects skeletal muscle and improves cardiac function in dystrophin-deficient mice; therefore, it was included in this study to evaluate the effects of lisinopril used with quercetin and NR. Our purpose was to determine the extent to which Q, NR, and Lis decreased dystrophic injury. We hypothesized that Q, NR, or Lis alone would improve muscle function and decrease histological injury and when used in combination would have additive effects. Muscle function of 11-mo-old DBA (healthy), D2-mdx (dystrophin-deficient), and D2-mdx mice was assessed after treatment with Q, NR, and/or Lis for 7 mo. To mimic typical pharmacology of patients with Duchenne muscular dystrophy, a group was treated with prednisolone (Pred) in combination with Q, NR, and Lis. At 11 mo of age, dystrophin deficiency decreased specific tension and tetanic force in the soleus and extensor digitorum longus muscles and was not corrected by any treatment. Dystrophic muscle was more sensitive to contraction-induced injury, which was partially offset in the QNRLisPred group, whereas fatigue was similar between all groups. Treatments did not decrease histological damage. These data suggest that treatment with Q, NR, Lis, and Pred failed to adequately maintain dystrophic limb muscle function or decrease histological damage. NEW & NOTEWORTHY Despite a compelling rationale and previous evidence to the contrary in short-term investigations, quercetin, nicotinamide riboside, or Lisinopril, alone or in combination, failed to restore muscle function or decrease histological injury in dystrophic limb muscle from D2-mdx mice after long-term administration. Importantly, we also found that in the D2-mdx model, an emerging and relatively understudied model of Duchenne muscular dystrophy dystrophin deficiency caused profound muscle dysfunction and histopathology in skeletal muscle.
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Shelton, G. Diane, Katie M. Minor, Steven G. Friedenberg, Jonah N. Cullen, Ling T. Guo, and James R. Mickelson. "Current Classification of Canine Muscular Dystrophies and Identification of New Variants." Genes 14, no. 8 (July 29, 2023): 1557. http://dx.doi.org/10.3390/genes14081557.
Full textAbstract:
The spectrum of canine muscular dystrophies has rapidly grown with the recent identification of several more affected breeds and associated mutations. Defects include those in genes and protein products associated with the sarcolemma (dystrophin deficient X-linked muscular dystrophy and sarcoglycan-deficient limb–girdle muscular dystrophy) and with the extracellular matrix (collagen 6, laminin α2, and α-dystroglycan-deficient congenital muscular dystrophies). With the increasing application of whole genome sequencing and whole exome sequencing, the clinical and pathological spectra associated with specific neuromuscular genetic defects are constantly evolving. In this report, we provide a brief overview of the current status of gene defects reported in canine muscular dystrophies. We also report the causative mutations for novel forms of X-linked muscular dystrophy in Brittany spaniels and in a French bulldog.
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Thompson, Terri G., Yiu-Mo Chan, Andrew A. Hack, Melissa Brosius, Michael Rajala, Hart G. W. Lidov, Elizabeth M. McNally, Simon Watkins, and Louis M. Kunkel. "Filamin 2 (FLN2): A Muscle-specific Sarcoglycan Interacting Protein." Journal of Cell Biology 148, no. 1 (January 10, 2000): 115–26. http://dx.doi.org/10.1083/jcb.148.1.115.
Full textAbstract:
Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin–glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin–glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a γ- and δ-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy.
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Vieira, Natassia M., Janelle M. Spinazzola, Matthew S. Alexander, Yuri B. Moreira, Genri Kawahara, Devin E. Gibbs, Lillian C. Mead, Sergio Verjovski-Almeida, Mayana Zatz, and Louis M. Kunkel. "Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy." Proceedings of the National Academy of Sciences 114, no. 23 (May 22, 2017): 6080–85. http://dx.doi.org/10.1073/pnas.1703556114.
Full textAbstract:
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these “escaper” dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.
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Burkin, Dean J., Gregory Q. Wallace, Kimberly J. Nicol, David J. Kaufman, and Stephen J. Kaufman. "Enhanced Expression of the α7β1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice." Journal of Cell Biology 152, no. 6 (March 19, 2001): 1207–18. http://dx.doi.org/10.1083/jcb.152.6.1207.
Full textAbstract:
Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and α7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the α7β1 integrin can compensate for the absence of dystrophin, we expressed the rat α7 chain in mdx/utr−/− mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the α7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr−/− mice. Concomitant with the increase in the α7 chain, its heterodimeric partner, β1D, was also increased in the transgenic animals. Transgenic expression of the α7BX2 chain in the mdx/utr−/− mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering α7β1 integrin–mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr−/− mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the α7β1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr−/− and α7BX2-mdx/utr−/−mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.
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Lewis, Caroline, Harald Jockusch, and Kay Ohlendieck. "Proteomic Profiling of the Dystrophin-Deficient MDX Heart Reveals Drastically Altered Levels of Key Metabolic and Contractile Proteins." Journal of Biomedicine and Biotechnology 2010 (2010): 1–20. http://dx.doi.org/10.1155/2010/648501.
Full textAbstract:
Although Duchenne muscular dystrophy is primarily classified as a neuromuscular disease, cardiac complications play an important role in the course of this X-linked inherited disorder. The pathobiochemical steps causing a progressive decline in the dystrophic heart are not well understood. We therefore carried out a fluorescence difference in-gel electrophoretic analysis of 9-month-old dystrophin-deficient versus age-matched normal heart, using the established MDX mouse model of muscular dystrophy-related cardiomyopathy. Out of 2,509 detectable protein spots, 79 2D-spots showed a drastic differential expression pattern, with the concentration of 3 proteins being increased, including nucleoside diphosphate kinase and lamin-A/C, and of 26 protein species being decreased, including ATP synthase, fatty acid binding-protein, isocitrate dehydrogenase, NADH dehydrogenase, porin, peroxiredoxin, adenylate kinase, tropomyosin, actin, and myosin light chains. Hence, the lack of cardiac dystrophin appears to trigger a generally perturbed protein expression pattern in the MDX heart, affecting especially energy metabolism and contractile proteins.
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Suelves, Mònica, Berta Vidal, Antonio L. Serrano, Marc Tjwa, Josep Roma, Roser López-Alemany, Aernout Luttun, et al. "uPA deficiency exacerbates muscular dystrophy in MDX mice." Journal of Cell Biology 178, no. 6 (September 4, 2007): 1039–51. http://dx.doi.org/10.1083/jcb.200705127.
Full textAbstract:
Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.
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Sun, Chengmei, Luoan Shen, Zheng Zhang, and Xin Xie. "Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update." Genes 11, no. 8 (July 23, 2020): 837. http://dx.doi.org/10.3390/genes11080837.
Full textAbstract:
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.