Motion og Endoplasmatisk Retikulum Stress

Nyproducerede proteiner i vores celler er kæder. Disse kæder skal foldes i en 3-dimensionel struktur. Dette sker i cellens Endoplasmatiske Reticulum (ER).

Når kroppen stresses fysisk, ophobes misfoldede (fejlagtigt foldede) proteiner. Dette udløser ER stress, som aktiverer det ufoldede protein respons (UPR).

Velfungerende ER stress og UPR i balance er sunde, normale reaktioner i vores celler. Men hvis mængden af ER stress er for stor, eller der er noget galt med vores ER stress respons, bliver vi svækket eller direkte syge.

ER og mitokondrier arbejder tæt sammen i vores celler. En ER dysfunktion vil påvirke mitokondrierne, og en mitokondrie dysfunktion vil påvirke ER. For overskuelighedens skyld vil jeg kun omtale ER stress.

De fysiske stress faktorer, der kan udløse ER stress er (1, 2):

• Infektioner
• Motion
• Kost med højt fedtindhold
• Sult
• Aldring
• Tab af calcium ioner fra ER

Link til figur 1 i reference 2, som viser en skematisk oversigt over ovennævnte faktorer:

https://pmc.ncbi.nlm.nih.gov/articles/PMC5548649/figure/F1/

At løfte vægte i et fitness center eller at løbe en tur kan aktivere ER stress og UPR. Efter hvile normaliseres situationen i cellerne, hvis man er rask vel at mærke.

Moderat, regelmæssig motion styrker kroppen og dæmper ER stress responset. MEN selv når raske mennesker overtræner og ikke får udhvilet, så belastes muskler og ER i muskelcellerne.

Der findes forskellige biokemiske stiveje i ER responset, som aktiveres ved motion. Dette er grundigt beskrevet i reference 1. Artiklen redegør for hvordan kost og forskellig typer motion påvirker ER responset.

På side 6 i reference 1 er noget interessant information fra et studie af mus: Motion ved lav intensitet og på tom mave kan ikke inducere ER stress.

Citat fra reference 1 (jeg har fremhævet den vigtige sætning):  "Different intensities and volumes og treadmill running modulate the UPR, but according to Jamart et al, this activation depends on nutritional condition. A single bout of treadmill running with low intensity (ie. approximately 55% VO2max) in the fed state increased Atf4 and Xbp1 expressions and the eIF2-alpha phosphorylation but decreased Ddit3 expression. When the exercise was performed in the fasted state, no differences in Xbp1s and Ddit3 expressions eIF2-alpha phosphorylation were visualized. For this reason, the authors conclude that low-intensity exercise cannot induse ER stress in fasted circumstances. Further studies should investigate the mechanism responsible for the lack of UPR activation during exercise in the fasted state."

Referencer

1) Marafon BB, Pinto AP, Ropelle ER, de Moura LP, Cintra DE, Pauli JR, da Silva ASR. Muscle endoplasmic reticulum stress in exercise. Acta Physiol (Oxf). 2022 May;235(1):e13799. doi: 10.1111/aphna.13799. Epub 2022 Feb 21. PMID: 35152547.

https://onlinelibrary.wiley.com/doi/10.1111/apha.13799

2) Bohnert KR, McMillan JD, Kumar A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J Cell Physiol. 2018 Jan;233(1):67-78. doi: 10.1002/jcp.25852. Epub 2017 May 16. PMID: 28177127; PMCID: PMC5548649.

https://onlinelibrary.wiley.com/doi/10.1002/jcp.25852

3) Jamart C, Naslain D, Gilson H, Francaux M. Higher activation of autophagy in skeletal muscle of mice during endurance exercise in the fasted state. Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E964-74. doi: 10.1152/ajpendo.00270.2013. Epub 2013 Aug 20. PMID: 23964069.
https://pubmed.ncbi.nlm.nih.gov/23964069/

Endoplasmatisk retikulum protein 29 er dysreguleret hos ME patienter

Af forrige blog indlæg: 

Dysregulering af Endoplasmatisk Retikulum stress responset hos ME patienter efter motion (1).

fremgik det, at Enoplasmatisk Retikulum protein 29 (ERP29) er dysreguleret i vesikler fra ME patienter efter motion. 

I et preprint af en ny artikel:

Charting the Circulating Proteome in ME/CFS. Cross System Profiling and Mechanistic insights (2).

har man undersøgt protein indholdet i serum fra ME patienter, og her dukker ERP29 også op.

ERP29 er nr 7 på listen over opregulerede proteiner. Dette fremgår af figur 1E på side 31 i artiklen.

Det eneste som vi kan bruge denne observation til lige nu, er at vi skal holde øje med forskning i ERP29. Så nu kommer lidt ERP29 viden.

ERP29 og ER stress

ERP29 er opreguleret under ER stress (ERS). Ved ER stress ophobes misfolde proteiner. Dette udløser det ufoldede protein respons (UPR) (3).

Citat fra artikel 3:
"While it is logical to hypothesize that ERp29 is predominantly upregulated during ERS to facilitate stabilization of its clients for their eventual exit from the ER, there are also data suggesting that ERp29 may play a role in the underlying pathways that regulate and facilitate UPR and ERS."

I figur 3 fra reference 3 er ERP29s mulige rolle i ER stress og UPR anskueliggjort:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7506106/figure/F3/

Mere viden om ERP29

Regulatory role of endoplasmic reticulum resident chaperone protein ERp29 in anti-murine β-coronavirus host cell response

Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes

Phenylbutyrate restricts murine β-coronavirus infectivity and limits virus-induced demyelination in vivo

Endoplasmic reticulum protein 29 negatively regulates platelet functions and thrombosis in mice

Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning

ERp29 Attenuates Nicotine-Induced Endoplasmic Reticulum Stress and Inhibits Choroidal Neovascularization

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

Referencer

1) Glass KA, Giloteaux L, Zhang S, Hanson MR. Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome. Clin Transl Med. 2025 May;15(5):e70346. doi: 10.1002/ctm2.70346. PMID: 40465195; PMCID: PMC12135887.
https://pubmed.ncbi.nlm.nih.gov/40465195/

2) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights
August Hoel, Fredrik Hoel, Sissel Elisabeth Furesund Dyrstad, Henrique Chapola, Ingrid Gurvin Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Karl Albert Brokstad, Hans-Peter Marti, Olav Mella, Øystein Fluge, Karl Johan Tronstad
medRxiv 2025.05.28.25328245; doi: https://doi.org/10.1101/2025.05.28.25328245
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

https://www.medrxiv.org/content/10.1101/2025.05.28.25328245v1

3) Brecker M, Khakhina S, Schubert TJ, Thompson Z, Rubenstein RC. The Probable, Possible, and Novel Functions of ERp29. Front Physiol. 2020 Sep 8;11:574339. doi: 10.3389/fphys.2020.574339. PMID: 33013490; PMCID: PMC7506106.

https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.574339/full

Dysregulering af Endoplasmatisk Retikulum stress responset hos ME patienter efter motion

Efter motion af ME patienter viser proteiner fra vesikler isoleret fra serum, at der er dysregulering af energimetabolismen, komplementsystemet og Endoplasmatisk Retikulum (ER) stress responset (1):

Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome

Basisviden: Ekstracellulære veksikler (EV) er små "beholdere" med protein, der udskilles fra forskellige celletyper, f. eks. muskel- og immunceller. Efter motion kan EV indeholde proteiner, der anvendes til ændret metabolisme, inflammations processer og vedligehold af muskler.

Beskrivelse af forsøget:
EV blev isoleret fra plasma fra 10 mænd med ME:

• før motion
• 15 minutter efter motion
• 24 timer efter motion

Der blev ligledes isoleret EV fra plasma fra en matchende kontrolgruppe. Figur fra artiklen (1):

Resultater fra forsøget:

Jeg vil kun gennemgå resultater vedrørende ER stress responset. Proteiner der vedrører ER funktion viste noget interessant. Forholdet mellem proteinniveauet i vesiklerne efter 24 timer og 15 minutter  (24 h/15 min ratio) viste en positiv korrelation til graden af Post Exertional Malaise (PEM)

Citat fra artiklen:
"A core symptom of ME/CFS is PEM, which we found to correlate significantly with changes in several proteins following exercise. Specifically, the 24 h/15 min ratio of 10 proteins showed a positive correlation with the severity of PEM experienced by subjects 24 h postexercise (Figure 6A; Table S9)."

Her er figur 6A (1):

I øverste venstre hjørne ses et STRING protein-protein interaktions netværk. Cirklerne angiver proteinerne og stregerne viser forskellige slags interaktioner mellem proteinerne.

Her er nogle citater fra artiklens afsnit 4.4, som hedder "Endoplasmic reticulum stress and protein misfolding are dysregulated in ME/CFS and associated with PEM":

"We found 10 proteins whose 24 h/15 min ratios positively correlated with the severity of PEM in ME/CFS patients at 24 h postexercise (Figure 6A). These proteins form a highly interconnected PPI network related to endoplasmic reticulum (ER) stress management and protein folding. Several of these proteins were also found to be differentially abundant between ME/CFS patients and controls."

"The presence of HSPA5 (a master regulator of ER homeostasis), PPIB, DNAJB11 (an ER protein that is a co‐chaperone for HSPA5), and PDIA4 as central hubs in the PPI network (Figure 6A) suggests that disruptions in protein folding and ER stress management may play a significant role in the pathophysiology of PEM. The involvement of PDIA4, TXNDC5, and ERP29, all members of the PDI family, underscores the importance of proper protein folding and cellular stress responses in maintaining homeostasis under conditions of chronic or post‐exertional stress."

Det vil sige, at proteinet HSPA5 er helt centralt for ligevægten i Endoplasmatisk Retikulum.

Sammenhæng til anden forskning

..og det var netop HSPA5, ER stress og motionsintolerance, der dukkede op i dette studiet (2):

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

som er beskrevet i dette blogindlæg:

Årsagen til ME patienters motionsintolerance er fundet

Og ER stress dukkede op i DecodeME studiet (3), og det er beskrevet i dette blogindlæg:

DecodeME genet CCPG1 er involveret i endoplasmatisk retikulum stress

ME forskere er opmærksomme på ER stress i ME sygdomsmekanismen

Forskerne bag vesikel studiet er opmærksom på sammenhængen til WASF3 studiet, idet de skriver (citat reference 1):

"To the best of our knowledge, only one study (min bemærkning: det er WASF3 studiet, som de omtaler) showed a maladaptive ER stress response in ME/CFS, in muscle tissue. Authors found decreased levels of HSPA5 (also known as BiP/GRP78) along with increased levels of ER stress marker eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3/PERK) in skeletal muscle tissue from ME/CFS patients compared with controls, which is consistent with ER stress response failure. Simultaneously, they found an increase in Wiskott‐Aldrich syndrome protein family member 3 (WASF3), which is regulated by the ER stress response, and showed that transgenic mice overexpressing WASF3 exhibited impaired exercise tolerance. WASF3 was detected in EVs in this study, but it was not detected in enough samples to meet the criteria for analysis."

Referencer

1) Glass KA, Giloteaux L, Zhang S, Hanson MR. Extracellular vesicle proteomics uncovers energy metabolism, complement system, and endoplasmic reticulum stress response dysregulation postexercise in males with myalgic encephalomyelitis/chronic fatigue syndrome. Clin Transl Med. 2025 May;15(5):e70346. doi: 10.1002/ctm2.70346. PMID: 40465195; PMCID: PMC12135887.

https://pubmed.ncbi.nlm.nih.gov/40465195/

2) 1) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159. 

https://www.pnas.org/doi/10.1073/pnas.2302738120

3) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

DecodeME genet CCPG1 er involveret i endoplasmatisk retikulum stress

DecodeME artiklen (1) udpegede en række gener, der kan være involveret i ME sygdomsmekanismen. Dette er beskrevet her: DecodeME studiet afslører variationer i DNAet fra ME patienter

Et af generne er CCPG1 - cell cycle progression 1.

DecodeME artiklen oplyser følgende om CCPG1 (1):

"CCPG1 mediates the selective degradation of the endoplasmic reticulum by autophagy (62). This is a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection (63)."


Sådan virker CCPG1

Endoplasmatisk retikulum (ER) er et netværk af membraner i vores celler, der er opdelt i en ru del og en glat del. Den ru del er dækket af ribosomer og er involveret i proteinsyntese, modifikation og transport af proteiner. Den glatte del producerer lipider, såsom kolesterol og steroider, og spiller en rolle i afgiftning af skadelige stoffer

Retikulofagi eller ER-fagi er den selektive nedbrydning af dele af det endoplasmatiske retikulum. Herved kan skadede dele af ER'et fjernes fra vores celler. Denne proces spiller en rolle i celle stress responset. 

Når virus inficerer vores celler, anvender de ER til eget brug. Vores celler reagere med ER stress og retikulofagi for at bekæmpe virus.

CCPG1 er én ud af flere receptorer, der styrer retikulofagi. 

Figur 2 fra artiklen Reticulophagy and viral infection viser en skematisk oversigt over nogle retikulofagi receptorer (2):

Figur 4 fra artiklen viser, hvordan ER stress øger transkription af CCPG1 (2):

Kort forklaring til figur 4. Ved ER stress ophobes misfoldede proteiner. Så fjernes HSPA5 fra ERN1. ERN1 aktivere XBP1, som sørger for at MIST1 produceres. Og MIST1 sørger for CCPG1 produceres. 

Hvis der er en variation i ME patienters CCPG1, kan reticulofagi responset været nedsat og evnen til at bekæmpe virus være nedsat.

ER stress i ME sygdomsmekanismen

ER stress er et spændende område i ME forskningen, da det er sat i relation til motionsintolerance. Det er beskrevet i et tidligere blogindlæg:

Årsagen til ME patienters motionsintolerance er fundet

Forfattere bag artiklen om WASF3 og motionsintolerance har også skrevet en artikel om mitokondriedysfunktion:

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Herfra vil jeg bringe et citat, som viser, at ME forskerne allerede tidligere har tænkt på sammenhængen mellem ME, virus, ER stress, mitokondriedysfunktion og sat det i sammenhæng til WASF3 og motionsintolerance:

"The endoplasmic reticulum is a membranous organelle whose major function is the synthesis of luminal/membrane proteins and their maturation, sorting and delivery. However, the ER apparatus can be usurped by viruses for utilization at different stages of their life cycle such as during viral entry, protein synthesis, replication, assembly and exit from the cell (87). As expected with such extraneous activities, viral infections can disrupt ER homeostasis and stress the system. Interestingly, ER stress has been associated with oxidative stress and the two often coexist in various pathological conditions but the underlying mechanism has remained elusive (13). Our observation that ER stress induces WASF3 through a post-transcriptional mechanism, disrupting mitochondrial function and thereby causing oxidative stress, could provide an explanation for this phenomenon (72, 115). It also suggests that the increased WASF3 in ME/CFS could be part of an immune response to a perceived stimulus."


Så lad os glædes over, at ME puslespilsbrikkerne bliver flere og flere og passer sammen.

Referencer:

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Wilson A, McCormick C. Reticulophagy and viral infection. Autophagy. 2025 Jan;21(1):3-20. doi: 10.1080/15548627.2024.2414424. Epub 2024 Oct 23. PMID: 39394962; PMCID: PMC11702952.
https://pubmed.ncbi.nlm.nih.gov/39394962/

3) Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Jul 1;40(4):0. doi: 10.1152/physiol.00056.2024. Epub 2025 Feb 17. PMID: 39960432; PMCID: PMC12151296.
https://pubmed.ncbi.nlm.nih.gov/39960432/

DecodeME genet SUDS3 nedregulerer inflammation i mikroglia

DecodeME artiklen (1) udpegede en række gener, der kan være involveret i ME sygdomsmekanismen. Dette er beskrevet her:

DecodeME studiet afslører variationer i DNAet fra ME patienter

Et af generne er SUDS3 - SIN3A corepressor complex component SDS3. (SUDS3 kaldes også for SDS3).

DecodeME artiklen oplyser følgende om SUDS3 (1):

"SUDS3 encodes a protein that is a negative regulator of microglial inflammation (51). ME/CFS genetic risk at this locus, therefore, could act to suppress the microglial inflammatory response."


Sådan virker SIN3A komplekset

SIN3A er et proteinkompleks, der kan binde sig til enzymer kaldet histone deacetylaser (HDAC'er) og herved kan SIN3A histonedeacetylase komplekset "slukke" for udvalgte gener. 

Histoner er de spoler, hvorpå vores DNA er oprullet. Tilgængeligheden af DNAet styres ved at påsætte/fjerne acetylgrupper. 

Når acetyl grupperne fjernes, bliver det sværere for cellens maskineri at få adgang til DNA'et og transskribere generne. Man siger også, at gen ekspressionen er nedsat, og der bliver herved dannet mindre protein ud fra genet. 

HAT: Histone acetyltransferase sætter acetyl-grupper på histonerne. Dvs genet "tændes".
HDAC: Histone deacetylase fjerner acetyl-grupper fra histonerne. Dvs genet "slukkes"

Læs mere om dette i wikipedia: Histone acetylation and deacetylation


Sådan ser SIN3A komplekset ud

SIN3A komplekset har mange forskellige funktioner. Det kan man læse om i artiklen (2):

Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex

I figur 1A fra artiklen (2) kan man se en skematisk tegning af SIN3A komplekset med SUDS3 som komponent:

Sådan virker SUDS3 i SIN3A corepressor komplekset

Et studie har undersøgt SUDS3's funktion i mikroglia, som er hjernens immunceller. Man aktiverede mikroglia fra mus med Lipo Poly Sakkarid (LPS), som er en komponent fra bakterier. LPS anvendes ofte i laboratorieforsøg for at inducere inflammation. Ved inflammation aktiveres en biokemisk stivej, der hedder p38 MAP Kinase signalvejen. Denne proces kan begynde med at en anden kinase MAP3K5 (også kaldet ASK1) aktiveres. 

Forsøget viste, at MAP3K5 regulerede inflammationen i mikroglia igennem p38 MAP kinase stivejen. Og i celler uden SUDS3 var det inflammatoriske respons opreguleret. 

Dvs  SUDS3 regulerer mikroglial inflammation ved at fungere som en negativ regulator af p38 MAPK-signalvejen. Det sker primært ved at kontrollere ekspressionen af ​​den MAP3K5. Dette opnås ved at danne et kompleks med HDAC1, der binder til MAP3K5-promotoren, hvilket hæmmer MAP3K5-gen ekspressionen og dermed den inflammatoriske respons i mikroglia.

Figur 7C i artiklen (3) viser dette skematisk. (Husk at MAP3K5 = ASK1):

SIN3A og MAP3K5 regulerer mange forskellige processer 

Nu kan man stille spørgsmålet om SIN3A HDAC komplekset eller MAP3K5 påvirker andre processer i ME sygdomsmekanismen?

Det vil kræve mere ME forskning at finde ud af. Mens vi venter på det, kan se se om der er anden forskning i SIN3A eller MAP3K5, som måske kunne være relevant for ME.

Sammenhæng mellem SIN3A og hypoxia kunne måske være relevant?

Citat fra nedenstående artikel (4):

The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia

"SIN3A interference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells. Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction."

"Interestingly, recent reports in Saccharomyces and Drosophila (78) demonstrate that loss of SIN3 affect mitochondrial activity, suggesting an evolutionarily conserved role for SIN3 in the control of cellular energy production. Further studies will be required to test the role of SIN3A in the changes induced by hypoxia on mitochondrial function."

En anden artikel (5) viser MAP3K5 er involveret i ER stress og skade på endothelium. Det er ikke til at vide om SIN3A komplekset er involveret i processen.

Citat fra artiklen (5):

FOXP1‑induced DUSP12 alleviates vascular endothelial cell inflammation and oxidative stress injury induced by ox‑LDL via MAP3K5 signaling pathway

"Ox-LDL induced endoplasmic reticulum stress and endothelial cell injury through inflammasome activation mediated by the MAP3K5/NLRP3 signaling pathway (25)."

Referencer:

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Adams GE, Chandru A, Cowley SM. Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex. Biochem J. 2018 Dec 14;475(24):3921-3932. doi: 10.1042/BCJ20170314. PMID: 30552170; PMCID: PMC6295471.

https://pubmed.ncbi.nlm.nih.gov/30552170/

3) Shen J, Lai W, Li Z, Zhu W, Bai X, Yang Z, Wang Q, Ji J. SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway. Inflamm Res. 2024 Sep;73(9):1547-1564. doi: 10.1007/s00011-024-01913-5. Epub 2024 Jul 15. PMID: 39008037; PMCID: PMC11349808.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11349808/

https://link.springer.com/article/10.1007/s00011-024-01913-5

4) Tiana M, Acosta-Iborra B, Puente-Santamaría L, Hernansanz-Agustin P, Worsley-Hunt R, Masson N, García-Rio F, Mole D, Ratcliffe P, Wasserman WW, Jimenez B, Del Peso L. The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia. Nucleic Acids Res. 2018 Jan 9;46(1):120-133. doi: 10.1093/nar/gkx951. PMID: 29059365; PMCID: PMC5758878.

https://pubmed.ncbi.nlm.nih.gov/29059365/

5) Li Y, Gu L, Zhou J, Han C, Zang W. FOXP1‑induced DUSP12 alleviates vascular endothelial cell inflammation and oxidative stress injury induced by ox‑LDL via MAP3K5 signaling pathway. Exp Ther Med. 2023 Aug 3;26(3):450. doi: 10.3892/etm.2023.12149. PMID: 37614418; PMCID: PMC10443057.

https://pubmed.ncbi.nlm.nih.gov/37614418/

OLFM4 bliver opreguleret i forbindelse med inflammation og hypoxia i hjernen

OLFM4 er et af DecodeME generne og er beskrevet her:

DecodeME genet OLFM4 styrer en del af balancen i immunforsvaret

Og her er mere viden om den rolle OLFM4 spiller i immunforsvaret.

I et forsøg udsatte man rotter for inflammation ved at indsprøjte Lipo Poly Sakkarid (LPS). Herefter blev rotterne udsat for hypoxia (HI). Disse rotter er i artiklen omtalt som LPS/HI gruppen (1).

Efter 24 timer blev rotterne aflivet, og der blev udført transcriptomics på microglia isoleret fra hjernen. Forsøget er anskueliggjort i figur 1 fra reference 1: 

Resultatet viste opregulering af gener involveret i neutrofil kemotaxi. Hos raske individder krydser de neutrofile ikke blod-hjerne barrieren, men ved LPS/HI sker der aktivering af microglia og rekruttering af leucocytter til hjernen. 

Olfactomedin 4, Selectin P og Serpin family E member 1 var nogle af de gener med størst opregulering. 

Citat fra artiklen (1): "Comparing expression levels of the four groups, Olfm4, Selp, Serpine 1, Il1r2 and Pawr were found to be the significantly upregulated genes in LPS/HI injury (Fig. 4). These findings can indicate that these genes are specific markers for inflammation-sensitized HI conditions in microglia. Olfm4 was significantly upregulated in the LPS/HI group compared to other groups. It is a glycoprotein known to be upregulated in inflamed tissue and to interact with MMP9 [47]. MMP9 expression was also upregulated in microglia from both HI groups and has been shown to act over Notch signaling pathway via p53 [47]. Olfm4 is expressed in high amounts in neutrophils and can serve as a biomarker for the severity of several bacterial or viral infections [48]."

På baggrund af denne viden kan man stille spørgsmålet om Decode ME variationen i genet OLFM4 har noget at gøre med mikroglia aktivering i ME???

Reference

1) Bremer AS, Henschel N, Burkard H, Bernis ME, Ulas T, Sabir H. Transcriptomic profile of microglia following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats suggests strong contribution to neutrophil chemotaxis and activation. J Neuroinflammation. 2025 Jul 19;22(1):189. doi: 10.1186/s12974-025-03516-1. PMID: 40684206; PMCID: PMC12276676.

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-025-03516-1

DecodeME genet OLFM4 styrer en del af balancen i immunforsvaret

DecodeME artiklen (1) udpegede en række gener, der kan være involveret i ME sygdomsmekanismen. Dette er beskrevet her: DecodeME studiet afslører variationer i DNAet fra ME patienter

Et af generne er OLFM4 - olfactomedin 4.

DecodeME artiklen oplyser følgende om OLFM4 (1):

"Olfactomedin-4 (OLFM4) suppresses antibacterial and inflammatory responses by binding to neutrophil cationic proteins and neutralises their ability to kill bacteria and form immunogenic complexes with DNA (61)."

Denne viden om OLFM4 er fra artiklen (2):

OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins

De neutrofile udgør en del af immunforsvaret. En undergruppe af de neutrofile udskiller OLFM4. 

Aktiverede neutrofile udskiller en lang række proteiner. Disse proteiner kan være:

• positivt ladede (kationer)
• negativt ladede (anioner)
• neutrale

Figur 1A og 1B fra ovennævnte artikel (2) viser en oversigt over disse proteiner:

De positivt ladede proteiner hedder på engelsk, Neutrophil Cationic Proteins (NCPs). NCPs kan via deres positive ladning interagere med mikroorganismer og skade dem. OLFM4 kan via sin negative ladning dæmpe processen. Herved holdes immunforsvaret i balance. 

OLFM4 er opreguleret i mange virale og bakterielle infektioner. OLFM4 anses for at være en biomarkør for, hvor alvorligt infektionen udvikler sig. Højt niveau af OLFM4 er forbundet med højere dødelighed ved livstruende infektioner (3).

Det store spørgsmål er, hvordan en mulig DNA variation i OLFM4 genet påvirker ME sygdomsmekanismen? Her må vi vent på mere forskning. I mellemtiden kan vi se, hvad det norske studie af proteiner i serum fra ME patienter viser. 

Artiklen over studiet findes som et prerprint (4):

Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

Der var ikke nedsat niveau af neutrofile, men der var nedsat niveau af proteiner, som de neutrofile kan udskille. Det tyder på udmattelse eller nedsat aktivitet af neutrofile. Citat fra side 13 artiklen (4):

"Regarding the reduction of bone marrow proteins, decreased protein release from neutrophils appears to be a plausible explanation. Many of the granulocyte-related proteins found to be decreased in the patients are associated with neutrophil granules, stimulated secretion, and NETs, suggesting that changes in neutrophil maturation and/or activation states occur in ME/CFS (59). These cells release DNA and proteins such as MPO, BPI, histones, and granular proteins when activated upon infection. The release of these proteins is not restricted to the NET process, and other aspects of neutrophil activity and phenotypes may be involved (60). Since standard clinical blood cell counts did not indicate detectable abnormalities in the circulating numbers of the main leukocyte classes in the ME/CFS patients, the proteomics data may suggest that functional changes are present, which may include exhaustion or suppression of neutrophil activity. This represents a mechanistic element that also is likely to involve other immune cell types, as well as cells in the blood vessel walls (61)."

Går man ind i supplerende tabel 2 og søger på OLFM4 ser man, at der ikke er forskel på niveauet af OLFM4 i serum fra ME patienter og raske kontrol personer. 

Man skal være opmærksom på, at OLFM4 også findes i knoglemarv, tarm og prostata. Kan OLFM4 spille en rolle i tarmen i ME sygdomsmekanismen? Det bliver spændende at se, hvad ME forskerne finder ud af.


Mere viden om OLFM4:

Olfactomedin-4 in digestive diseases: A mini-review

OLFM4 modulates intestinal inflammation by promoting IL-22+ILC3 in the gut

Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells

Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion, epithelial–mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer

Referencer:

1) Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome
https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1
Genetics Delivery Team, Thibaud Boutin, Andrew D. Bretherick, Joshua J. Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L. Samms, Veronique Vitart, Project and Cohort Delivery Team, Øyvind Almelid, Tom Baker, Malgorzata Clyde, Anne Connolly, Diana Garcia, Shona M. Kerr, Claire Tripp, Jareth C. Wolfe, Patient and Public Involvement, Jackie Goold, Gemma Hoyes, Sian Leary, Simon J. McGrath, Julie Milton, Anna Redshaw, Jim M. Wilson, Marketing and Communications Team, Helen Baxter, Danielle Boobyer, Claire Dransfield, Daphne Lamirel, Isabel Lewis, Nina Muirhead, Ella Ponting, Charles Shepherd, Alice Turner, University of Edinburgh Team, Sumy V. Baby, Sjoerd Beentjes, John Ireland, Ava Khamseh, Ewan McDowall, David Perry, Joshua Slaughter, Genetic Epidemiology of ME/CFS Consortium, Erik Abner, Cindy G. Boer, Estonian Biobank Research Team, Sarah Finer, Genes & Health Research Team, Hele Haapaniemi, Hanna M. Ollila, Beth Pollack, Judith Rosmalen, Erika Romppanen, Sirine Saafi, Richa Saxena, Nasa Sinnott-Armstrong, Anniina Tervi, Lea Urpa, Jesse Valliere, David A. van Heel, Management Team, Sonya Chowdhury, Andy Devereux-Cooke, Chris P. Ponting
medRxiv 2025.08.06.25333109; doi: https://doi.org/10.1101/2025.08.06.25333109
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Vandenberghe-Dürr S, Gilliet M, Di Domizio J. OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins. Cell Rep. 2024 Oct 22;43(10):114863. doi: 10.1016/j.celrep.2024.114863. Epub 2024 Oct 11. PMID: 39396234.

https://pubmed.ncbi.nlm.nih.gov/39396234/

3) Liu W, Rodgers GP. Olfactomedin 4 Is a Biomarker for the Severity of Infectious Diseases. Open Forum Infect Dis. 2022 Feb 8;9(4):ofac061. doi: 10.1093/ofid/ofac061. PMID: 35291445; PMCID: PMC8918383.
https://pubmed.ncbi.nlm.nih.gov/35291445/

4) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights

August Hoel, Fredrik Hoel, Sissel Elisabeth Furesund Dyrstad, Henrique Chapola, Ingrid Gurvin Rekeland, Kristin Risa, Kine Alme, Kari Sørland, Karl Albert Brokstad, Hans-Peter Marti, Olav Mella, Øystein Fluge, Karl Johan Tronstad

medRxiv 2025.05.28.25328245; doi: https://doi.org/10.1101/2025.05.28.25328245

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

https://www.medrxiv.org/content/10.1101/2025.05.28.25328245v1