loading...| Preferred Name |
Muscular Dystrophies |
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| Synonyms |
PathwayType: signaling Tissue: muscle Description: Duchenne muscular dystrophy (DMD) is a muscle disorder caused by various mutations in the gene coding for dystrophin. Pathway is built manually using published studies. CellType: muscle cell Organ_System: musculoskeletal system NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. In DMD, muscle membranes become more fragile and sensitive to mechanical forces. Stretch occurring during exercise can tear membranes of muscle cells allowing extracellular Ca2+ to enter the cell. Stretch-activated Ca2+ channels (SACs) are another source of extra Ca2+ in DMD. Membrane tears and SACs along with the other candidate channels and factors responsible for Ca2+ storage and buffering inside the cells cause severe Ca2+ overload. Outcome effects: Elevated Ca2+ activates Ca2+-dependent proteases such as calpains and therefore increases proteolysis. Many of the muscular structural proteins contain cleavage site for calpains. Calpain cleavage also changes the activity of nitric oxide synthase (NOS) and Ca2+ leak channels. NOS signaling is decreased in dystrophin-deficient muscles, as NOS requires a functional dystrophin for proper localization. It weakens the nitric oxide (NO) protective effect and contributes to oxidative stress which is another prominent feature of dystrophin deficiency. All of these factors contribute to increased cell death and inflammation, resulting in muscular dystrophy. Currently, there is no cure for DMD; however treatment options include anti-inflammatory drugs. NO donors and Ca2+ blockers have been tested in animal models. The up-regulation of utrophin (UTRN), a protein that can partially replace dystrophin in DGC, could also benefit affected muscle. The induction of calcineurin-NFATC1 signaling enhances the expression of UTRN. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Link: https://mammal-profservices.pathwaystudio.com/app/sd?urn=urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 Source: Diseases |
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| ID |
urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 |
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PS:PathwayType PS:Description PS:Tissue PS:Link PS:CellType PS:Organ_System PS:NodeType PS:Notes PS:Source |
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| has_exact_synonym |
PathwayType: signaling Tissue: muscle Description: Duchenne muscular dystrophy (DMD) is a muscle disorder caused by various mutations in the gene coding for dystrophin. Pathway is built manually using published studies. CellType: muscle cell Organ_System: musculoskeletal system NodeType: Pathway Notes: Headnote: Muscular dystrophy refers to a group of progressive muscular disorders with muscle weakening and breakdown being the major symptom. Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy caused by various mutations in the gene coding for dystrophin. The disease is generally inherited in the X-linked recessive manner and manifests before the age of six in boys. The disease eventually leads to inability to walk, weakness of breathing due to respiratory muscle weakness and severely decreased life expectancy. Signaling description: Dystrophin is crucial for the assembly of the dystrophin glycoprotein complex (DGC) that spans the cell membrane providing a link between extracellular matrix and cytoskeleton and serves as a docking site for the members of various signaling cascades. The absence of a functional dystrophin, results in the inability to form a full-fledged DGC, which leads to increased cell membrane fragility and impaired signaling, both of which can cause an elevation in intracellular calcium (Ca2+) levels. In DMD, muscle membranes become more fragile and sensitive to mechanical forces. Stretch occurring during exercise can tear membranes of muscle cells allowing extracellular Ca2+ to enter the cell. Stretch-activated Ca2+ channels (SACs) are another source of extra Ca2+ in DMD. Membrane tears and SACs along with the other candidate channels and factors responsible for Ca2+ storage and buffering inside the cells cause severe Ca2+ overload. Outcome effects: Elevated Ca2+ activates Ca2+-dependent proteases such as calpains and therefore increases proteolysis. Many of the muscular structural proteins contain cleavage site for calpains. Calpain cleavage also changes the activity of nitric oxide synthase (NOS) and Ca2+ leak channels. NOS signaling is decreased in dystrophin-deficient muscles, as NOS requires a functional dystrophin for proper localization. It weakens the nitric oxide (NO) protective effect and contributes to oxidative stress which is another prominent feature of dystrophin deficiency. All of these factors contribute to increased cell death and inflammation, resulting in muscular dystrophy. Currently, there is no cure for DMD; however treatment options include anti-inflammatory drugs. NO donors and Ca2+ blockers have been tested in animal models. The up-regulation of utrophin (UTRN), a protein that can partially replace dystrophin in DGC, could also benefit affected muscle. The induction of calcineurin-NFATC1 signaling enhances the expression of UTRN. Highlighted proteins: Proteins with decreased expression or activity are highlighted in blue. Source: Diseases |
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| id |
urn:agi-pathway:uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 |
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| label |
Muscular Dystrophies |
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| notation |
uuid-8f059474-e0fb-425e-96d8-7d15e7758aa8 |
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| prefLabel |
Muscular Dystrophies |
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| treeView |
urn:agi-folder:m urn:agi-folder:(under_review)_muscular_dystrophies urn:agi-folder:musculoskeletal_system urn:agi-folder:muscles urn:agi-folder:muscular_dystrophies |
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| subClassOf |
urn:agi-folder:m urn:agi-folder:(under_review)_muscular_dystrophies urn:agi-folder:musculoskeletal_system urn:agi-folder:muscles urn:agi-folder:muscular_dystrophies |