Affected pathways in Duchenne muscular dystrophy (Homo sapiens)

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1, 18, 2961, 14, 19, 298, 31, 322353211320Loss of Membrane IntegrityMacrophage29, 402, 29NucleusMyocyte cytosolmPTPInhibitionConversionLoss of mitochondriaCatalysisFibroblast ActivationModificationLegendMAMsStimulationInefficient Myofiber RepairMembrane TearMitochondriaSR8Ca2+FibrosisProteasome degradationMMP2IP3R3ParkinPathwayCaspase 9Sig-1RInflammatory pathwayCalpain-3VDAC1SERCA1ProteoglycansTOMIP3R1Unfolded protein responseVDAC1[Ca2+]mitoMMP9MitophagyMCUbADT2Phospholipase A2ROSGlycoproteinsRYR1Dystrophin deficiencyDMD(+mutation)IP3R2TGF-β1Ca2+CyP-DNecrosisROSGRP75SOCEMCUDMDCa2+NOX2ATPOxidative stressDigestion of cell membraneApoptosisLactateInflammatory response252927212234424178, 38Protein orGeneProductMetabolitePathwayTGFBR2TGFBR1SMAD4SMAD2SMAD3SERPINE1SCX9, 3235PLAU32FibronectinCollagenAng 232RAS-MAPK pathway10, 32IL-615IL-1α15SMAD232SMAD332NOX413, 28, 30CTGF26TNF-αAGTR11532Dystrobrevin alphaSyntrophin beta-1alpha sarcoglycanSarcospanDystrophinDystroglycan 1Disassembled Dystrophin-associated glycoprotein complex (DAPC)STIM1Orai1Ca2+2, 7, 14, 19, 29...mTORMuscular regeneration3615, 36RYR124CAC1FCAC1SCACB2CACB1CA2D1CCG1LTCCDMD (+mutations)19, 39Calstabin-12, 14Sarcolipin16


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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  1. Chen X, Li Y; ''Role of matrix metalloproteinases in skeletal muscle: migration, differentiation, regeneration and fibrosis.''; Cell Adh Migr, 2009 PubMed Europe PMC Scholia
  2. Tulangekar A, Sztal TE; ''Inflammation in Duchenne Muscular Dystrophy-Exploring the Role of Neutrophils in Muscle Damage and Regeneration.''; Biomedicines, 2021 PubMed Europe PMC Scholia
  3. Zabłocka B, Górecki DC, Zabłocki K; ''Disrupted Calcium Homeostasis in Duchenne Muscular Dystrophy: A Common Mechanism behind Diverse Consequences.''; Int J Mol Sci, 2021 PubMed Europe PMC Scholia
  4. Burr AR, Molkentin JD; ''Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.''; Cell Death Differ, 2015 PubMed Europe PMC Scholia
  5. Tauffenberger A, Fiumelli H, Almustafa S, Magistretti PJ; ''Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling.''; Cell Death Dis, 2019 PubMed Europe PMC Scholia
  6. Burr AR, Molkentin JD; ''Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.''; Cell Death Differ, 2015 PubMed Europe PMC Scholia
  7. Song Y, Yao S, Liu Y, Long L, Yang H, Li Q, Liang J, Li X, Lu Y, Zhu H, Zhang N; ''Expression levels of TGF-β1 and CTGF are associated with the severity of Duchenne muscular dystrophy.''; Exp Ther Med, 2017 PubMed Europe PMC Scholia
  8. Klingler W, Jurkat-Rott K, Lehmann-Horn F, Schleip R; ''The role of fibrosis in Duchenne muscular dystrophy.''; Acta Myol, 2012 PubMed Europe PMC Scholia
  9. Mareedu S, Million ED, Duan D, Babu GJ; ''Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies.''; Front Physiol, 2021 PubMed Europe PMC Scholia
  10. Kharraz Y, Guerra J, Pessina P, Serrano AL, Muñoz-Cánoves P; ''Understanding the process of fibrosis in Duchenne muscular dystrophy.''; Biomed Res Int, 2014 PubMed Europe PMC Scholia
  11. Miyatake S, Shimizu-Motohashi Y, Takeda S, Aoki Y; ''Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.''; Drug Des Devel Ther, 2016 PubMed Europe PMC Scholia
  12. Ismaeel A, Kim JS, Kirk JS, Smith RS, Bohannon WT, Koutakis P; ''Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review.''; Int J Mol Sci, 2019 PubMed Europe PMC Scholia
  13. Shkrob MA, Pyatnitskiy MA, Golovatenko-Abramov PK, Kotelnikova EA; ''Pathways Disturbed in Duchenne Muscular Dystrophy''; 10.2174/978160805437411201010104, 2012 PubMed Europe PMC Scholia
  14. Hammers DW; ''NOX4 inhibition promotes the remodeling of dystrophic muscle.''; JCI Insight, 2022 PubMed Europe PMC Scholia
  15. Blake DJ, Weir A, Newey SE, Davies KE; ''Function and genetics of dystrophin and dystrophin-related proteins in muscle.''; Physiol Rev, 2002 PubMed Europe PMC Scholia
  16. Dalkilic I, Kunkel LM; ''Muscular dystrophies: genes to pathogenesis.''; Curr Opin Genet Dev, 2003 PubMed Europe PMC Scholia
  17. Reid AL, Alexander MS; ''The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy.''; Life (Basel), 2021 PubMed Europe PMC Scholia
  18. Knollmann BC; ''New roles of calsequestrin andtriadin in cardiac muscle.''; J Physiol, 2009 PubMed Europe PMC Scholia
  19. Hammers DW; ''NOX4 inhibition promotes the remodeling of dystrophic muscle.''; JCI Insight, 2022 PubMed Europe PMC Scholia
  20. Shkrob MA, Pyatnitskiy MA, Golovatenko-Abramov PK, Kotelnikova EA; ''Pathways Disturbed in Duchenne Muscular Dystrophy''; Doi: 10.2174/978160805437411201010104, 2012 PubMed Europe PMC Scholia
  21. Kasza KE, Zallen JA; ''Dynamics and regulation of contractile actin-myosin networks in morphogenesis.''; Curr Opin Cell Biol, 2011 PubMed Europe PMC Scholia
  22. Björn C Knollmann; ''New roles of calsequestrin and triadin in cardiac muscle''; , 2009 PubMed Europe PMC Scholia
  23. Dubinin MV, Talanov EY, Tenkov KS, Starinets VS, Mikheeva IB, Belosludtsev KN; ''Transport of Ca(2+) and Ca(2+)-dependent permeability transition in heart mitochondria in the early stages of Duchenne muscular dystrophy.''; Biochim Biophys Acta Bioenerg, 2020 PubMed Europe PMC Scholia
  24. Choi MH, Ow JR, Yang ND, Taneja R; ''Oxidative Stress-Mediated Skeletal Muscle Degeneration: Molecules, Mechanisms, and Therapies.''; Oxid Med Cell Longev, 2016 PubMed Europe PMC Scholia
  25. Lacourpaille L, Hug F, Guével A, Péréon Y, Magot A, Hogrel JY, Nordez A; ''New insights on contraction efficiency in patients with Duchenne muscular dystrophy.''; J Appl Physiol (1985), 2014 PubMed Europe PMC Scholia
  26. Budzinska M, Zimna A, Kurpisz M; ''The role of mitochondria in Duchenne muscular dystrophy.''; J Physiol Pharmacol, 2021 PubMed Europe PMC Scholia
  27. Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L; ''The role of oxidative stress during inflammatory processes.''; Biol Chem, 2014 PubMed Europe PMC Scholia
  28. Harr MW, Distelhorst CW; ''Apoptosis and autophagy: decoding calcium signals that mediate life or death.''; Cold Spring Harb Perspect Biol, 2010 PubMed Europe PMC Scholia
  29. Moratal C, Arrighi N, Dechesne CA, Dani C; ''Control of Muscle Fibro-Adipogenic Progenitors by Myogenic Lineage is Altered in Aging and Duchenne Muscular Dystrophy.''; Cell Physiol Biochem, 2019 PubMed Europe PMC Scholia
  30. Ismaeel A, Kim JS, Kirk JS, Smith RS, Bohannon WT, Koutakis P; ''Role of Transforming Growth Factor-β in Skeletal Muscle Fibrosis: A Review.''; Int J Mol Sci, 2019 PubMed Europe PMC Scholia
  31. Nogami K, Maruyama Y, Sakai-Takemura F, Motohashi N, Elhussieny A, Imamura M, Miyashita S, Ogawa M, Noguchi S, Tamura Y, Kira JI, Aoki Y, Takeda S, Miyagoe-Suzuki Y; ''Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice.''; Hum Mol Genet, 2021 PubMed Europe PMC Scholia
  32. Rodriguez-Gonzalez M, Lubian-Gutierrez M, Cascales-Poyatos HM, Perez-Reviriego AA, Castellano-Martinez A; ''Role of the Renin-Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy.''; Int J Mol Sci, 2020 PubMed Europe PMC Scholia
  33. Lindahl M, Bäckman E, Henriksson KG, Gorospe JR, Hoffman EP; ''Phospholipase A2 activity in dystrophinopathies.''; Neuromuscul Disord, 1995 PubMed Europe PMC Scholia
  34. Mareedu S, Million ED, Duan D, Babu GJ; ''Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies.''; Front Physiol, 2021 PubMed Europe PMC Scholia
  35. Chambers PJ, Juracic ES, Fajardo VA, Tupling AR; ''Role of SERCA and sarcolipin in adaptive muscle remodeling.''; Am J Physiol Cell Physiol, 2022 PubMed Europe PMC Scholia
  36. Burr AR, Molkentin JD; ''Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.''; Cell Death Differ, 2015 PubMed Europe PMC Scholia
  37. Driscoll KE; ''Macrophage inflammatory proteins: biology and role in pulmonary inflammation.''; Exp Lung Res, 1994 PubMed Europe PMC Scholia
  38. Trabold O, Wagner S, Wicke C, Scheuenstuhl H, Hussain MZ, Rosen N, Seremetiev A, Becker HD, Hunt TK; ''Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing.''; Wound Repair Regen, 2003 PubMed Europe PMC Scholia
  39. Angebault C, Panel M, Lacôte M, Rieusset J, Lacampagne A, Fauconnier J; ''Metformin Reverses the Enhanced Myocardial SR/ER-Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice.''; Front Cell Dev Biol, 2020 PubMed Europe PMC Scholia
  40. Harisseh R, Chatelier A, Magaud C, Déliot N, Constantin B; ''Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of α1-syntrophin and PLC/PKC in SOCE regulation.''; Am J Physiol Cell Physiol, 2013 PubMed Europe PMC Scholia
  41. Nagamine Y, Medcalf RL, Muñoz-Cánoves P; ''Transcriptional and posttranscriptional regulation of the plasminogen activator system.''; Thromb Haemost, 2005 PubMed Europe PMC Scholia
  42. Shkrob MA, Pyatnitskiy MA, Golovatenko-Abramov PK, Kotelnikova EA; ''Pathways Disturbed in Duchenne Muscular Dystrophy''; From Knowledge Networks to Biological Models, 2012 PubMed Europe PMC Scholia
  43. Meyer P, Notarnicola C, Meli AC, Matecki S, Hugon G, Salvador J, Khalil M, Féasson L, Cances C, Cottalorda J, Desguerre I, Cuisset JM, Sabouraud P, Lacampagne A, Chevassus H, Rivier F, Carnac G; ''Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients.''; Int J Mol Sci, 2021 PubMed Europe PMC Scholia
  44. Kharraz Y, Guerra J, Pessina P, Serrano AL, Muñoz-Cánoves P; ''Understanding the process of fibrosis in Duchenne muscular dystrophy.''; Biomed Res Int, 2014 PubMed Europe PMC Scholia
  45. Miyatake S, Shimizu-Motohashi Y, Takeda S, Aoki Y; ''Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.''; Drug Des Devel Ther, 2016 PubMed Europe PMC Scholia
  46. Hammers DW; ''NOX4 inhibition promotes the remodeling of dystrophic muscle.''; JCI Insight, 2022 PubMed Europe PMC Scholia
  47. Tulangekar A, Sztal TE; ''Inflammation in Duchenne Muscular Dystrophy-Exploring the Role of Neutrophils in Muscle Damage and Regeneration.''; Biomedicines, 2021 PubMed Europe PMC Scholia

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)
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
CCG1GeneProductENSG00000108878 (Ensembl) Voltage-dependent calcium channel subunit gamma-1
CTGFGeneProductCCN2 (HGNC)
Ca2+ MetaboliteHMDB0000464 (HMDB)
Ca2+MetaboliteHMDB0000464 (HMDB)
Calpain-3ProteinCAPN3 (HGNC)
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)
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)
Muscular regenerationPathwayWP4172 (WikiPathways)
NOX2GeneProductP04839 (Uniprot-TrEMBL)
NOX4GeneProductNOX4 (HGNC)
NecrosisPathwayWP2513 (WikiPathways)
Orai1GeneProductENSG00000276045 (Ensembl)
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)
STIM1GeneProductENSG00000167323 (Ensembl)
SarcolipinProteinENSG00000170290 (Ensembl)
SarcospanGeneProductSSPN (HGNC)
Sig-1RProteinSIGMAR1 (HGNC)
Syntrophin beta-1GeneProductSNTB1 (HGNC)
TGF-β1GeneProductENSG00000105329 (Ensembl)
TGFBR1 GeneProductTGFBR1 (HGNC)
TGFBR2GeneProductTGFBR2 (HGNC)
TNF-αGeneProductENSG00000232810 (Ensembl)
TOMProteinTOMM20 (HGNC)
Unfolded protein responsePathwayWP1939 (WikiPathways)
VDAC1 ProteinVDAC1 (HGNC)
VDAC1ProteinVDAC1 (HGNC)
[Ca2+]mitoMetaboliteHMDB0000464 (HMDB)
alpha sarcoglycanGeneProductSGCA (HGNC)
mTORPathwayWP4923 (WikiPathways)

Annotated Interactions

No annotated interactions

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