Affected pathways in Duchenne muscular dystrophy (Homo sapiens)

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ArcPathVisio Brace Ellipse EndoplasmicReticulum GolgiApparatus HexagonPathVisio MimDegradation Mitochondria Octagon PentagonPathVisio Rectangle RoundedRectangle SarcoplasmicReticulum TriangleEquilateralEast TrianglePathVisio none Fibro-adipogenic progenitorsLoss of membraneintegrityMacrophageCatalysisSarcoplasmicreticulumMuscle stiffnessMembrane tearNucleusMuscle cellmPTPStimulationMitochondrial dysfunctionConversionInefficient myofiber repairMAMsLoss of mitochondriaSustained muscle contractionFibrosis pathwayFibroblast activationInhibitionLegendMitochondriaImpaired musclecontractionModificationInflammatory pathwayOxidative stressCASP9Lactate[Ca2+]mitoUnfolded proteinresponseCa2+RYR1Ca2+FibroblastdifferentiationNOX2PLA2G2AROSNecrosisROSSOCECa2+FibrosisGLI1ApoptosisDystrophin deficiencyDMDSERCA1ParkinpathwayTNNI1CAPN3MitophagyProteasome degradationDMD (+ mutation)TGFB1Digestion of cell membraneMuscle contractionATPInflammatory pathwayOPNInflammatory responseGRP75PPIFVDAC1ADT2VDAC1TOMM20SIGMAR1MCUMCUBProteoglycansGlycoproteinsIP3R2IP3R3IP3R1MMP2MMP9TGFBR2TGFBR1SMAD4SMAD2SMAD3SERPINE1SCXPLAUFibronectinCollagenAng 2RAS-MAPK pathwayIL6IL1BTNFSMAD2SMAD3NOX4CTGFAGTR1DTNASNTB1SGCASSPNDMDDAG1Disassembled Dystrophin-associated glycoprotein complex (DAPC)STIM1ORAI1Ca2+mTORMuscular regenerationRYR1CACNA1FCACNA1SCACNB2CACNB1CACNA2D1CACNG1L-type calcium channel (LTCC)DMD (+mutations)FKBP1ASLNDAMPsM1 macrophageM2 macrophageIL1AIL6TNFIL10NFkBNFKBIASOCECAPN3Platelet-activating factorLeukotrienesPhospholipidmembrane digestionProstaglandinsTGFB1PLA2G4AROSCa2+Inflammatory pathwaysInflammatory pathwaysAutophagyMuscular regenerationNFkBTRPC3TRPC1TRPC6Ca2+Ca2+Sodium regulatorsNa+Ca2+Na+Ca2+Ca2+FibrosisNecrosisROSCASQ 1TRDNCAMK2DAMPK1AMPK2NeutrophilOxidative stressNecrosisCl-H2O2NONEHOClL-ArginineNOS2MPOHOClFibrinogenFGGFGBFGAName: Affected pathways in Duchenne muscular dystrophyOrganism: Homo sapiens


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.

Acknowledgments: Bria Jackson, Amaia Alvarez van Schie, Otto Rämö, Tuneille Adelaar

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Ontology Terms

Bibliography

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History

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External references

DataNodes

View all...
Name  ↓Type  ↓Database reference  ↓Comment  ↓
ADT2GeneProductSLC25A5 (HGNC)
AGTR1GeneProductAGTR1 (HGNC)
AMPK1GeneProductENSG00000132356 (Ensembl)
AMPK2ProteinENSG00000162409 (Ensembl)
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)
CACNA1FGeneProductENSG00000102001 (Ensembl) Voltage-dependent L-type calcium channel subunit alpha-1F
CACNA1SGeneProductENSG00000081248 (Ensembl) Voltage-dependent L-type calcium channel subunit alpha-1S
CACNA2D1GeneProductENSG00000153956 (Ensembl) Voltage-dependent calcium channel subunit alpha-2/delta-1. Only isoform 1 is found in the skeletal muscles
CACNB1GeneProductENSG00000067191 (Ensembl) Voltage-dependent L-type calcium channel subunit beta-1. Only isoform 2 is present in skeletal muscles
CACNB2GeneProductENSG00000165995 (Ensembl) Voltage-dependent L-type calcium channel subunit beta-2
CACNG1GeneProductENSG00000108878 (Ensembl) Voltage-dependent calcium channel subunit gamma-1
CAMK2DProteinENSG00000145349 (Ensembl) "CaMK2" originally
CAPN3ProteinCAPN3 (HGNC) "Calpain-3" originally
CAPN3GeneProductENSG00000092529 (Ensembl) "Calpain-3" in original source
CASP9ProteinCASP9 (HGNC) "Caspase 9" originally
CASQ 1GeneProductCASQ1 (HGNC)
CTGFGeneProductCCN2 (HGNC)
Ca2+ MetaboliteHMDB0000464 (HMDB)
Ca2+MetaboliteHMDB0000464 (HMDB)
Cl-MetaboliteHMDB0000492 (HMDB)
CollagenMetaboliteCHEBI:3815 (ChEBI)
DAG1GeneProductDAG1 (HGNC) "Dystroglycan 1" originally
DMD (+ mutation)GeneProductDMD (HGNC)
DMD (+mutations)GeneProductENSG00000198947 (Ensembl)
DMDGeneProductDMD (HGNC) "Dystrophin" originally
DTNAGeneProductDTNA (HGNC) "Dystrobrevin alpha" originally
Digestion of cell membranePathwayWP5122 (WikiPathways)
Dystrophin deficiencyGeneProductDMD (HGNC)
FGAGeneProductFGA (HGNC)
FGBGeneProductFGB (HGNC)
FGGGeneProductFGG (HGNC)
FKBP1AGeneProductENSG00000088832 (Ensembl) "Calstabin-1" originally. 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
Fibroblast differentiationPathwayWP5312 (WikiPathways)
FibronectinMetaboliteCHEBI:5058 (ChEBI)
FibrosisPathway
GLI1ProteinGLI1 (HGNC) "GL1" originally
GRP75ProteinP38646 (Uniprot-TrEMBL)
GlycoproteinsProteinGP2 (HGNC)
H2O2MetaboliteHMDB0003125 (HMDB)
HOClMetaboliteHMDB0001050 (HMDB)
IL10GeneProductENSG00000136634 (Ensembl)
IL1AGeneProductENSG00000115008 (Ensembl)
IL1BGeneProductENSG00000125538 (Ensembl)
IL6GeneProductENSG00000136244 (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
L-ArginineMetaboliteHMDB0000517 (HMDB)
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/
MCUBProteinMCUB (HGNC)
MCUProteinMCU (HGNC)
MMP2ProteinMMP2 (HGNC)
MMP9ProteinMMP9 (HGNC)
MPOGeneProductENSG00000005381 (Ensembl) Myeloperoxidase (MPO) is a potent enzyme which catalyses the production of hypochlorous acid (HOCl) when hydrogen peroxide (H2O2) and chloride ions (Cl-) are present within the neutrophil.
MitophagyPathwayWP3549 (WikiPathways)
Muscle contraction PathwayWP383 (WikiPathways)
Muscular regenerationPathwayWP4172 (WikiPathways)
NEGeneProductENSG00000197561 (Ensembl) Neutrophil elastase (NE) is a type of serine protease which promotes the formation of neutrophil extracellular traps (NETs), which themselves function to trap invading microbes but also cuase tissue damage as collateral. Although possibly playing a role in the pathophysiology of DMD, it is not yet confirmed if NETs contribute to the muscle damage
NFKBIAGeneProductENSG00000100906 (Ensembl) "IκBα" in original source
NFkBGeneProductENSG00000109320 (Ensembl)
NOMetaboliteHMDB0003378 (HMDB)
NOS2ProteinENSG00000007171 (Ensembl) "iNOS" in original source
NOX2GeneProductP04839 (Uniprot-TrEMBL)
NOX4GeneProductNOX4 (HGNC)
Na+MetaboliteHMDB0000588 (HMDB)
NecrosisPathwayWP2513 (WikiPathways)
NecrosisPathwayWP3380 (WikiPathways)
OPNGeneProductSPP1 (HGNC)
ORAI1GeneProductENSG00000276045 (Ensembl)
Oxidative stressPathway
Oxidative stressPathwayWP408 (WikiPathways)
PLA2G2AProteinPLA2G2A (HGNC) "Phospholipase A2" originally
PLA2G4AGeneProductENSG00000116711 (Ensembl) "Phospholipase A2" in original source
PLAUGeneProductPLAU (HGNC) Also known as Urokinase-type plasminogen inhibitor (uPA)
PPIFProteinPPIF (HGNC) "CyP-D" originally
Parkin pathwayPathwayWP2359 (WikiPathways)
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
SGCAGeneProductSGCA (HGNC) "alpha sarcoglycan" originally
SIGMAR1ProteinSIGMAR1 (HGNC) "Sig-1R" originally
SLNProteinENSG00000170290 (Ensembl) "Sarcolipin" originally
SMAD2 GeneProductSMAD2 (HGNC)
SMAD3 GeneProductSMAD3 (HGNC)
SMAD4ProteinSMAD4 (HGNC)
SNTB1GeneProductSNTB1 (HGNC) "Syntrophin beta-1" originally
SOCEPathway
SOCEGeneProductSARAF (HGNC)
SSPNGeneProductSSPN (HGNC) "Sarcospan" originally
STIM1GeneProductENSG00000167323 (Ensembl)
Sodium regulatorsProteinThe increased permeability can also induce Na influx to the cells, allongside Ca influx. THe cells prioritize the efflux of Na, indusing further Ca influx
TGFB1GeneProductENSG00000105329 (Ensembl)
TGFBR1 GeneProductTGFBR1 (HGNC)
TGFBR2GeneProductTGFBR2 (HGNC)
TNFGeneProductENSG00000232810 (Ensembl)
TNNI1ProteinTNNI1 (HGNC) "Troponin" originally
TOMM20ProteinTOMM20 (HGNC) "TOM" originally
TRDNGeneProductTRDN (HGNC) "Triadin" originally
TRPC1GeneProductENSG00000144935 (Ensembl) Short transient receptor potential channel 1
TRPC3GeneProductENSG00000138741 (Ensembl) Short transient receptor potential channel 3
TRPC6GeneProductENSG00000137672 (Ensembl) Short transient receptor potential channel 6
Unfolded protein responsePathwayWP1939 (WikiPathways)
VDAC1 ProteinVDAC1 (HGNC)
VDAC1ProteinVDAC1 (HGNC)
[Ca2+]mitoMetaboliteHMDB0000464 (HMDB)
mTORPathwayWP4923 (WikiPathways)

Annotated Interactions

No annotated interactions

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