Affected pathways in Duchenne muscular dystrophy (Homo sapiens)

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11, 23, 277, 23, 24, 27364220, 22, 384047382328103442914Fibro-Adipogenic ProgenitorsLoss of Membrane IntegrityMacrophage19, 231018, 23MitochondriaStimulationConversionInefficient Myofiber RepairmPTPLegendNucleusMuscle Stiffness Sustained Muscle ContractionMyocyte cytosolLoss of mitochondriaCatalysisModificationMAMsInhibitionSRMembrane TearFibroblast Activation2039Ca2+Caspase 9VDAC1ROSATPNecrosisOxidative stressInflammatory pathwayApoptosisDigestion of cell membraneCa2+Unfolded protein responseLactatePhospholipase A2MitophagyCalpain-3NOX2Proteasome degradationInflammatory responseParkinPathwayProteoglycansSOCEGRP75CyP-DMCUbDMD(+mutation)IP3R3RYR1ADT2TOMMMP9Muscle contraction VDAC1GlycoproteinsDystrophin deficiencyMMP2TGF-B1SERCA1Ca2+GL1FibroblastDifferentiationIP3R1MCUIP3R2DMDROSFibrosisTroponinSig-1R[Ca2+]mito13373044412330251020, 3245101731Protein orGeneProductMetabolitePathwayTGFBR2TGFBR1SMAD4SMAD2SMAD3SERPINE1SCX5, 38PLAU338FibronectinCollagenAng 238RAS-MAPK pathwayIL-626, 3821IL-1B21SMAD2SMAD33838NOX4CTGF8, 29, 432TNF-a21AGTR138Dystrobrevin alphaSyntrophin beta-1alpha sarcoglycanSarcospanDystrophinDystroglycan 1Disassembled Dystrophin-associated glycoprotein complex (DAPC)STIM1Orai17, 9, 12, 18, 23...Ca2+mTORMuscular regeneration3321, 33RYR145CAC1FCAC1SCACB2CACB1CA2D1CCG1LTCCDMD (+mutations)1, 7Calstabin-1Sarcolipin18, 246DAMPs121212, 23, 2412M1 MacrophageM2 Macrophage2121IL-1α21IL-6IL-102121NFkBIκBα12SOCE12Calpain-323, 3512, 23, 24Platelet-activating factorLeukotrienesPhospholipid MembraneDigestionProstaglandins23TGF-βTNF-α2121Phospholipase A223ROSCa2+Inflammatory pathwaysROS12, 23Inflammatory pathwaysAutophagy7, 12Muscular regeneration21NFkB16TRPC3TRPC1TRPC6Ca2+Ca2+Sodium regulators23Na+23Ca2+Na+2323Ca2+Ca2+23Fibrosis39NecrosisROSCASQ 1Triadin46


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 (ROS) and activation of proteases that can damage the cell structure of muscle fibers. The lack of the dystrophin protein affects essential components for muscle contraction namely the Disassembled Dystrophin-associated glycoprotein complex (DAPC) which disturbs the normal contraction-relaxation process of the muscle in DMD. Sustained contractions occur due to the high calcium influx causing muscle stiffness and fibrosis, which are known characteristics of DMD.

Indeed, fibrosis is commonly stimulated in dystrophic muscle cells as a result of the upregulation of several pro-fibrotic transcription factors such as SERPINE1, SCX and GL1. Hence, excessive amounts of collagen and fibronectin are produced, enhancing fibrosis.

All these events cause chronic inflammation in the muscle cell, attracting pro-inflammatory cytokines, chemokines and other inflammatory mediators. The chronic inflammation in DMD can further perpetuate muscle degeneration, fibrosis, and impaired muscle function.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
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

View all...
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)
AutophagyPathwayWP4923 (WikiPathways)
CA2D1GeneProductENSG00000153956 (Ensembl) Voltage-dependent calcium channel subunit alpha-2/delta-1. Only isoform 1 is found in the skeletal muscles
CAC1FGeneProductENSG00000102001 (Ensembl) Voltage-dependent L-type calcium channel subunit alpha-1F
CAC1SGeneProductENSG00000081248 (Ensembl) Voltage-dependent L-type calcium channel subunit alpha-1S
CACB1GeneProductENSG00000067191 (Ensembl) Voltage-dependent L-type calcium channel subunit beta-1. Only isoform 2 is present in skeletal muscles
CACB2GeneProductENSG00000165995 (Ensembl) Voltage-dependent L-type calcium channel subunit beta-2
CASQ 1GeneProductCASQ1 (HGNC)
CCG1GeneProductENSG00000108878 (Ensembl) Voltage-dependent calcium channel subunit gamma-1
CTGFGeneProductCCN2 (HGNC)
Ca2+ MetaboliteHMDB0000464 (HMDB)
Ca2+MetaboliteHMDB0000464 (HMDB)
Calpain-3ProteinCAPN3 (HGNC)
Calpain-3GeneProductENSG00000092529 (Ensembl)
Calstabin-1GeneProductENSG00000088832 (Ensembl)
  • Often, there is Ca2+ leakage from the RyRs in the SR, but this process is limited by calstabin-1. Calstabin-1 is a protein which has a high affinity for RyR, stimulated by the dystrophin. However, due to DMD mutations and thus reduction of dystrophin, the Calstabin-1 no longer binds with such a high affinity to the RyR, thus not blocking the calcium leakage
  • Type your comment here
Caspase 9ProteinCASP9 (HGNC)
CollagenMetaboliteCHEBI:3815 (ChEBI)
CyP-DProteinPPIF (HGNC)
DMD (+mutations)GeneProductENSG00000198947 (Ensembl)
DMD(+mutation)GeneProductDMD (HGNC)
DMDGeneProductDMD (HGNC)
Digestion of cell membranePathwayWP5122 (WikiPathways)
Dystrobrevin alphaGeneProductDTNA (HGNC)
Dystroglycan 1GeneProductDAG1 (HGNC)
Dystrophin deficiencyGeneProductDMD (HGNC)
DystrophinGeneProductDMD (HGNC)
Fibroblast DifferentiationPathwayWP5312 (WikiPathways)
FibronectinMetaboliteCHEBI:5058 (ChEBI)
FibrosisPathway
GL1ProteinGLI1 (HGNC)
GRP75ProteinP38646 (Uniprot-TrEMBL)
GlycoproteinsProteinGP2 (HGNC)
IL-10GeneProductENSG00000136634 (Ensembl)
IL-1BGeneProductENSG00000115008 (Ensembl)
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 pathways PathwayAlthough the immune response functions to heal cells and tissues after damage, often when there is chronic inflammation (as is the case in DMD), the immune cells and the cytokines they secrete end up having detrimental effects, such as promoting oxidative stress, autophagy and necrosis.
Inflammatory responsePathway
IκBαGeneProductENSG00000100906 (Ensembl)
LactateMetaboliteCHEBI:24996 (ChEBI)
LeukotrienesMetaboliteWhen leukocytes degrade phospholipid cell membranes, they also break down a type of phospholipid present called arachidonic acid. Break down of this arachidonic acid leads to the release of leukotrines, of which there are a wide variety. It is not yet known which exact leukotrine(s) play a role in the DMD pathophysiology, hence the use of the term "leukotrine" as a whole. Reference: Cuzzo B, Lappin SL. Physiology, Leukotrienes. [Updated 2022 Aug 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526114/
MCUProteinMCU (HGNC)
MCUbProteinMCUB (HGNC)
MMP2ProteinMMP2 (HGNC)
MMP9ProteinMMP9 (HGNC)
MitophagyPathwayWP3549 (WikiPathways)
Muscle contraction PathwayWP383 (WikiPathways)
Muscular regenerationPathwayWP4172 (WikiPathways)
NFkBGeneProductENSG00000109320 (Ensembl)
NOX2GeneProductP04839 (Uniprot-TrEMBL)
NOX4GeneProductNOX4 (HGNC)
Na+MetaboliteHMDB0000588 (HMDB)
NecrosisPathwayWP2513 (WikiPathways)
Orai1GeneProductENSG00000276045 (Ensembl)
Oxidative stress PathwayWP408 (WikiPathways)
PLAUGeneProductPLAU (HGNC) Also known as Urokinase-type plasminogen inhibitor (uPA)
Parkin PathwayPathwayWP2359 (WikiPathways)
Phospholipase A2GeneProductENSG00000116711 (Ensembl)
Phospholipase A2ProteinPLA2G2A (HGNC)
Phospholipid Membrane DigestionPathwayWP5122 (WikiPathways)
Platelet-activating factorMetaboliteHMDB0062195 (HMDB)
ProstaglandinsMetaboliteProstaglandins are released when phospholipid membranes are broken down. Although hundreds of prostaglandins exist which can influence the inflammatory pathways, no specific ones were highlighted with regards to the DMD pathophysiology
Proteasome degradation PathwayWP183 (WikiPathways)
ProteoglycansProteinPRG3 (HGNC)
RAS-MAPK pathwayPathwayWP400 (WikiPathways)
ROSMetaboliteThere are three primary reactive oxygen species (ROS) which are prevalent within the mitochondria, including the superoxide anions (O2-), the hydroxyl radicals (OH-) and the hydrogen peroxide (H2O2). These three, and possibly more, likely play a role in the DMD pathophysiology, however the exact type of ROS was not mentioned in the papers searched, thus the term ROS is used broadly here
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)
SOCEPathway
SOCEGeneProductSARAF (HGNC)
STIM1GeneProductENSG00000167323 (Ensembl)
SarcolipinProteinENSG00000170290 (Ensembl)
SarcospanGeneProductSSPN (HGNC)
Sig-1RProteinSIGMAR1 (HGNC)
Sodium regulatorsProtein
  • The increased permeability can also induce Na influx to the cells, allongside Ca influx. THe cells prioritize the efflux of Na, indusing further Ca influx
  • Type your comment here
Syntrophin beta-1GeneProductSNTB1 (HGNC)
TGF-B1GeneProductENSG00000105329 (Ensembl)
TGF-βGeneProductENSG00000105329 (Ensembl)
TGFBR1 GeneProductTGFBR1 (HGNC)
TGFBR2GeneProductTGFBR2 (HGNC)
TNF-aGeneProductENSG00000232810 (Ensembl)
TNF-αGeneProductENSG00000232810 (Ensembl)
TOMProteinTOMM20 (HGNC)
TRPC1GeneProductENSG00000144935 (Ensembl) Short transient receptor potential channel 1
TRPC3GeneProductENSG00000138741 (Ensembl) Short transient receptor potential channel 3
TRPC6GeneProductENSG00000137672 (Ensembl) Short transient receptor potential channel 6
TriadinGeneProductTRDN (HGNC)
TroponinProteinTNNI1 (HGNC)
Unfolded protein responsePathwayWP1939 (WikiPathways)
VDAC1 ProteinVDAC1 (HGNC)
VDAC1ProteinVDAC1 (HGNC)
[Ca2+]mitoMetaboliteHMDB0000464 (HMDB)
alpha sarcoglycanGeneProductSGCA (HGNC)
mTORPathwayWP4923 (WikiPathways)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5356"
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