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.