torsdag den 5. marts 2020

ME - a failure of inducing exercise tolerance?

ME hypothesis from Karolinska Institutet and Karolinska University Hospital in Sweden (1):

"ME - a failure of inducing disease tolerance upon chronic immune activation"

My question:
Is ME also a failure of inducing exercise tolerance?

At cellular level disease and inflammation result in increased reactive oxygen species (ROS) production. Stress-response pathways are countermeasures to ROS. Exercise also leads to increased ROS levels. The antioxidant enzyme superoxide dismutase 2 (SOD2) is one the primary mechanisms against ROS generated during exercise.

Quote from a review "Impact of oxidative stress on exercising skeletal muscle" (2):
"It is well established that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. These highly reactive molecules have many deleterious effects, such as a reduction of force generation and increased muscle atrophy. Since the discovery of exercise-induced oxidative stress several decades ago, evidence has accumulated that ROS produced during exercise also have positive effects by influencing cellular processes that lead to increased expression of antioxidants. These molecules are particularly elevated in regularly exercising muscle to prevent the negative effects of ROS by neutralizing the free radicals. In addition, ROS also seem to be involved in the exercise-induced adaptation of the muscle phenotype.

Chronic oxidative stress is associated with an increase in protein loss and muscle atrophy. High ROS levels cause a sustained activation of NF-κB and of FoxO which then activate two muscle-specific E3 ubiquitin ligases, atrogin-1 or muscle atrophy F-box (MAFbx) and muscle RING (Really Interesting New Gene)-finger protein 1 (MuRF-1) [52]. MAFbx and MuRF-1 then degrade various proteins, such as titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chain [53,54]. Recently, it was demonstrated that excessive oxidative stress also enhances the transcription factor C/EBP homology protein (CHOP). This transcription factor also enhances expression of MuRF1, which again results in increased protein degradation [35]."

It seems like ME patients have increased muscle protein degradation:

Increased serum and urine 3-methylhistidine in ME patients
http://followmeindenmark.blogspot.com/2020/03/increased-serum-and-urine-3.html

Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html

Proline, P5C and 4-hydroxyglutamate in ME
http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html

And do remember the transcription profile analysis of skeletal muscle from ME patients (3), quote:
"In an effort to establish which pathways might be involved in the onset and development of muscle symptoms, we used global transcriptome analysis to identify genes that were differentially expressed in the vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative balance, including superoxide dismutase 2, were altered, as were genes involved in energy production, muscular trophism and fiber phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS."

 Are the inflammatory reponse to disease and the adaptive response to exercise dysregulated in ME through the same pathways?

Reference

1) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
doi: https://doi.org/10.1101/2020.02.20.958249
https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract

2) Peter Steinbacher, Peter Eckl:
Impact of Oxidative Stress on Exercising Skeletal Muscle
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tirsdag den 3. marts 2020

Det inflammatoriske respons og induktion af sygdomstolerance er dysreguleret hos ME patienter

Forskere fra Karolinska Instituttet og Karolinska Universitetshospital har beskrevet en ME hypotese (1):

 "ME - a failure of inducing disease tolerance upon chronic immune activation"

 Sygdomstolerance er en overordnet betegnelse for en række stress-respons stiveje. Disse skal sørge for at begrænse skade fra patogene mikroorganismer og fra kroppens inflammationsproces.

 Vagusnerve og hjernestamme regulerer systemisk inflammation ved at skrue op eller ned for den inflammatoriske refleks. Nerver der fører fra kroppen (afferent vagus nerve endings) til hjernestamme sender besked om immunstatus i kroppen. Nerverne kan f.eks. sende besked om aktivitet fra patogene mikroorganismer i tarmen. Nerver der fører fra hjernestamme (efferente) til kroppen  sender signaler via acetylcholin om at dæmpe inflammationen. 

 Det er kendt viden, at påvirkning af vagusnerven kan dæmpe inflammatoriske tilstande.

 Forskerne fra Karolinska afprøvede Intranasal Mekanisk Stimulation (INMEST) på en gruppe ME patienter. INMEST udstyret består af et tyndt plasticrør, som placeres i næsen. Udstyret vibrerer og danner en turbulent luftstrøm. Dette inducerer en nervereflex, som påvirker vagusnerven. Behandlingen dæmpede nogle ME symptomer (men ikke fatigue), og blodprøver fra patienterne viste normalisering af inflammatoriske tilstande (1).

 En analyse af sygdomstoleranceprogrammer viste, at INMEST behandling opregulerede disse programmer.

 Forskerene påpegede, at årsagen til den manglende induktion af tolerance hos ME patienter skal klarlægges. Samtidig henviser de til forskningen i IDO2 enzymet, som netop er involveret i regulering af sygdomstolerance.

Mere viden om emnet kan findes her:

Neural Reflexes in Inflammation and Immunity
https://pubmed.ncbi.nlm.nih.gov/22665702-neural-reflexes-in-inflammation-and-immunity/

The Vagus Nerve and the Inflammatory Reflex--Linking Immunity and Metabolism
https://pubmed.ncbi.nlm.nih.gov/23169440-the-vagus-nerve-and-the-inflammatory-reflex-linking-immunity-and-metabolism/

Er der behandlingsmuligheder i lægemidler, der øger aktivitet i acetylcholin-stiveje?:
Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors
https://www.sciencedirect.com/science/article/abs/pii/S0028390820300861

Aryl Hydrocarbon Receptor Control of a Disease Tolerance Defence Pathway
https://pubmed.ncbi.nlm.nih.gov/24930766-aryl-hydrocarbon-receptor-control-of-a-disease-tolerance-defence-pathway/


Relevante blogindlæg:

Indånding af skimmel er noget, der kan gøre en ME/MCS patient ganske syg. IDO er med til at inducere tolerance i næsens slimhinder, og mutationer i IDO-generne har betydning for kroppens reaktion på skimmel infektion (AHR = Arylhydrocarbon receptor, MCS = multiple chemical sensitivity): 

IDO-ME hypotesen er forenelig med AHR-MCS hypotesen

Tryptofan metabolitten kynureninsyre har immunmodulerende egenskaber



Reference

1) Lucie S.T. Rodriguez, Christian Pou, Tadepally Lakshmikanth, Jingdian Zhang, Constantin Habimana Mugabo, Jun Wang, Jaromir Mikes, Axel Olin, Yang Chen, Joanna Rorbach, Jan-Erik Juto, Tie Qiang Li, Per Julin, Petter Brodin: Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance
doi: https://doi.org/10.1101/2020.02.20.958249
https://www.biorxiv.org/content/10.1101/2020.02.20.958249v1.abstract
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mandag den 2. marts 2020

Increased serum and urine 3-methylhistidine in ME patients

3-metylhistidine is a breakdown product of muscle contractile proteins. Serum or urine 3-methylhistidine is used as a biomarker of muscle protein degradation (1).

 Fluge et al found increased serum 3-metylhistidine in male ME patients (2).

 McGregor et al found increased urine 3-metylhistidine in post-exertional malaise (PEM) ME patients (1).

Quote from McGregor et al (1):
"The findings that the PEM is associated with a loss of metabolites, reduction in acetylation, deregulation of purine metabolism, increased contractile protein breakdown and bacteremia associated with exercise suggest that treatments such as graded exercise may be more detrimental than beneficial as claimed in some studies [39,40]. Until such time as these biological changes can be further investigated, the use of graded exercise as a therapy for those with severe forms of ME/CFS should be considered potentially harmful. In support of this, the use of graded exercise therapy has caused significant protest by ME/CFS sufferers as they see it as harmful [41,42]."


Further reading about possible breakdown of skeletal muscles in ME patients :

Proline, P5C and 4-hydroxyglutamate in ME
http://followmeindenmark.blogspot.com/2020/02/proline-p5c-and-4-hydroxyglutamate-in-me.html

Increased plasma N,N,N-trimethyl-L-alanyl-L-proline betaine in ME patients
https://followmeindenmark.blogspot.com/2020/02/increased-plasma-nnn-trimethyl-l-alanyl.html



Referencer
1) McGregor et al: Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases Diagnostics (Basel). 2019 Jul 4;9(3). pii: E70. doi: 10.3390/diagnostics9030070. https://www.ncbi.nlm.nih.gov/pubmed/31277442

2) Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276
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