Affected pathways in Duchenne muscular dystrophy (Homo sapiens)

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1, 15, 161828225, 6, 281914MacrophageMitochondriaMembrane TearmPTPInhibitionLoss of mitochondriaStimulationSRInefficient Myofiber RepairLegendConversionModificationFibroblast ActivationCatalysisMyocyte cytosolMAMs5DMDDystrophin deficiencyMMP9SOCESig-1R[Ca2+]CytoDigestion of cell membraneROSMMP2ATPFibrosisRYR1VDAC1SERCA1GlycoproteinsCa2+TGF-β1DMD(+mutation)ROSADT2MitophagyIP3R1Inflammatory responseApoptosisVDAC1NOX2Caspase 9IP3R3Ca2+MCUOxidative stressLactateProteasome degradationIP3R2TOMPhospholipase A2Inflammatory pathwayCyP-DGRP75Calpain-3ParkinPathwayProteoglycans[Ca2+]mitoNecrosisMCUbUnfolded protein response1235, 81710174212Protein orGeneProductMetabolitePathwayTGFBR2TGFBR1SMAD4SMAD2SMAD3SERPINE1SCX9, 28PLAU2628FibronectinCollagenAng 228RAS-MAPK pathway23, 28IL-627IL-1α27SMAD2SMAD32828NOX4CTGF11, 13, 2425TNF-αAGTR12728


Description

DMD (Duchenne muscular dystrophy) is a genetic disorder that primarily affects muscles in the body, causing progressive muscle weakness and wasting. It is caused by mutations in the DMD gene, which results in a deficiency or absence of the protein dystrophin, leading to muscle degeneration.

DMD is characterized by abnormal calcium levels resulting from dysfunction in the muscle cell membrane. This leads to the uncontrolled opening of the mitochondrial permeability transition pore (mPTP) which inhibits ATP synthesis and thus, drives the cell into apoptosis. This influx activates a cascade of harmful events, including increased production of reactive oxygen species and activation of enzymes that can damage the muscle fibers.

In DMD, calcium first enters the cell through a damaged sarcolemma, caused by a lack of dystrophin. This results in calcium overload in the cytoplasm of myocytes. Although mitochondria partially buffer the calcium overload, mitochondrial function declines and autophagy results in mitochondrial loss. This creates a positive feedback loop between ineffective myofiber repair and calcium influx, leading to dystrophic myocyte necrosis. Early stages of dystrophic cardiomyopathy involve intracellular calcium overload and increased NADPH oxidase type 2 (NOX2) ROS production. These conditions encourage cellular pathophysiological processes like apoptosis and necrosis, and may also initiate autophagy. As mitochondrial degeneration progresses, ATP production dramatically decreases.

This dysregulation of calcium is thought to contribute to the muscle degeneration and weakness observed in DMD.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
134500view06:45, 22 July 2024EgonwRemoved template comments
134392view19:27, 21 July 2024EweitzUpdate template comments
127722view18:50, 28 November 2023KhanspersModified title
127686view12:21, 22 November 2023EweitzModified title
127684view08:26, 22 November 2023TabbassidaloiiModified description
127683view08:25, 22 November 2023Tabbassidaloii
127681view23:16, 21 November 2023EweitzModified title
127623view20:23, 8 November 2023LarsgwRemove punctuation from bp:ID
127456view18:41, 3 October 2023Khanspersconnected interactions to anchors
126672view13:30, 11 June 2023Pauladewenter
126671view13:28, 11 June 2023Pauladewenter
126670view13:26, 11 June 2023Pauladewenter
126489view15:01, 9 May 2023PauladewenterNaming different parts of the pathway for clarity.
126488view13:24, 9 May 2023PauladewenterModified description
126467view05:22, 2 May 2023EgonwNot a mim-conversion
126463view19:12, 1 May 2023AlexanderPicofixed citations
126422view09:02, 28 April 2023EgonwMade two pathways clickable
126302view15:02, 20 April 2023Pauladewenter
126298view12:31, 20 April 2023Pauladewenter
126296view10:12, 20 April 2023Pauladewenter
126295view10:04, 20 April 2023Pauladewenter
126256view12:16, 18 April 2023PauladewenterModified description
126255view12:13, 18 April 2023PauladewenterModified description
126254view11:40, 18 April 2023PauladewenterModified description
126253view11:35, 18 April 2023Pauladewenter
126250view08:47, 18 April 2023Pauladewenter
126231view09:15, 17 April 2023Pauladewenter
126230view09:13, 17 April 2023Pauladewenter
126193view13:28, 14 April 2023Pauladewenter
126192view13:18, 14 April 2023PauladewenterModified title
126190view12:43, 14 April 2023Ash iyerChanged datanode to graphical element
126188view10:55, 14 April 2023Pauladewenter
126187view08:34, 14 April 2023Pauladewenter
126184view14:56, 13 April 2023Pauladewenter
126183view14:44, 13 April 2023PauladewenterNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADT2GeneProductSLC25A5 (HGNC)
AGTR1GeneProductAGTR1 (HGNC)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ang 2Metabolite172198 (PubChem-compound) "angiotensin 2 (Ang 2)" Peptide hormone; "Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells, kidney epithelial cells, and the brain). Angiotensin II acts on the central nervous system to increase vasopressin production, and also acts on venous and arterial smooth muscle to cause vasoconstriction. Angiotensin II also increases aldosterone secretion; it therefore acts as an endocrine, autocrine/paracrine, and intracrine hormone." Source: "https://en.wikipedia.org/wiki/Angiotensin#Angiotensin_II"
ApoptosisPathwayWP254 (WikiPathways)
CTGFGeneProductCCN2 (HGNC)
Ca2+ MetaboliteHMDB0000464 (HMDB)
Ca2+MetaboliteHMDB0000464 (HMDB)
Calpain-3ProteinCAPN3 (HGNC)
Caspase 9ProteinCASP9 (HGNC)
CollagenMetaboliteCHEBI:3815 (ChEBI)
CyP-DProteinPPIF (HGNC)
DMD(+mutation)GeneProductDMD (HGNC)
DMDGeneProductDMD (HGNC)
Digestion of cell membranePathwayWP5122 (WikiPathways)
Dystrophin deficiencyGeneProductDMD (HGNC)
FibronectinMetaboliteCHEBI:5058 (ChEBI)
FibrosisPathway
GRP75ProteinP38646 (Uniprot-TrEMBL)
GlycoproteinsProteinGP2 (HGNC)
IL-1αGeneProductENSG00000115008 (Ensembl)
IL-6GeneProductENSG00000136244 (Ensembl) In DMD, IL-6 is upregulated due to recurrent activation of the M1 macrophages by DAMPs. When upregulated for prolonged periods of time, the IL-6 will cause chronic inflammation and also reduce the population of the satellite cells that are needed for muscle regeneration.
IP3R1ProteinQ14643 (Uniprot-TrEMBL)
IP3R2ProteinITPR2 (HGNC)
IP3R3ProteinITPR3 (HGNC)
Inflammatory pathwayPathway
Inflammatory responsePathway
LactateMetaboliteCHEBI:24996 (ChEBI)
MCUProteinMCU (HGNC)
MCUbProteinMCUB (HGNC)
MMP2ProteinMMP2 (HGNC)
MMP9ProteinMMP9 (HGNC)
MitophagyPathwayWP3549 (WikiPathways)
NOX2GeneProductP04839 (Uniprot-TrEMBL)
NOX4GeneProductNOX4 (HGNC)
NecrosisPathwayWP2513 (WikiPathways)
Oxidative stress PathwayWP408 (WikiPathways)
PLAUGeneProductPLAU (HGNC) Also known as Urokinase-type plasminogen inhibitor (uPA)
Parkin PathwayPathwayWP2359 (WikiPathways)
Phospholipase A2ProteinPLA2G2A (HGNC)
Proteasome degradation PathwayWP183 (WikiPathways)
ProteoglycansProteinPRG3 (HGNC)
RAS-MAPK pathwayPathwayWP400 (WikiPathways)
ROSMetaboliteQ424361 (Wikidata)
RYR1GeneProductRYR1 (HGNC)
SCXProteinSCX (HGNC)
SERCA1ProteinATP2A1 (HGNC)
SERPINE1GeneProductSERPINE1 (HGNC) Also known as plasminogen activator inhibitor-1 PAI-1
SMAD2 GeneProductSMAD2 (HGNC)
SMAD3 GeneProductSMAD3 (HGNC)
SMAD4ProteinSMAD4 (HGNC)
SOCEGeneProductSARAF (HGNC)
Sig-1RProteinSIGMAR1 (HGNC)
TGF-β1GeneProductENSG00000105329 (Ensembl)
TGFBR1 GeneProductTGFBR1 (HGNC)
TGFBR2GeneProductTGFBR2 (HGNC)
TNF-αGeneProductENSG00000232810 (Ensembl)
TOMProteinTOMM20 (HGNC)
Unfolded protein responsePathwayWP1939 (WikiPathways)
VDAC1 ProteinVDAC1 (HGNC)
VDAC1ProteinVDAC1 (HGNC)
[Ca2+]CytoMetaboliteHMDB0000464 (HMDB)
[Ca2+]mitoMetaboliteHMDB0000464 (HMDB)

Annotated Interactions

No annotated interactions

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