1. Sign our petition calling on Cochrane to withdraw their review of Exercise Therapy for CFS here.
    Dismiss Notice
  2. Guest, the 'News in Brief' for the week beginning 18th March 2024 is here.
    Dismiss Notice
  3. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology, 2022, Hejbøl et al

Discussion in 'Long Covid research' started by SNT Gatchaman, Jun 7, 2022.

  1. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

    Messages:
    4,255
    Location:
    Aotearoa New Zealand
    Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology
    Eva K Hejbøl, Thomas Harbo, Jane Agergaard, Line B Madsen, Thomas H Pedersen, Lars J Østergaard, Henning Andersen, Henrik D Schrøder, Hatice Tankisi

    Background: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue.

    Methods: Sixteen patients (mean age:46 years) with post-COVID-19 complaints of fatigue, myalgia or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analysed with light and electron microscopy were taken.

    Results: Muscle weakness was present in 50%, myopathic electromyography in 75% while in all patients, there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of COX activity, subsarcollemmal accumulation and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T-lymphocytes and/or muscle fiber HLA-ABC expression. In 75%, capillaries were affected involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.

    Conclusions: The wide variety of histological changes in this study suggest that skeletal muscles may be a major target of SARS-CoV-2 causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Since most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

    Link (paywalled)
     
    EndME, merylg, livinglighter and 9 others like this.
  2. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,520
    Location:
    Aotearoa New Zealand
    This is interesting. I find the periodic muscle weakness I get one of the most intriguing symptoms. Until we can get some idea of the content of the paper itself, here's some background on the non-paywalled stuff.

    Researchers:
    Danish researchers, most from Aarhus University Hospital
    ("Per Fink is head Professor of The Research Clinic for Functional Disorders and Psychosomatics at Aarhus Universitetshospital in Denmark" - potentially making for interesting tea room chats)
    The authors seem to have a background in relevant things like myopathy in myasthenia gravis and polyneuropathy.

    Sampling and study design:
    The sample isn't random - there was probably selection of post-Covid patients reporting muscle weakness. 16 patients isn't a big sample, so there is the risk that at least some of the participants have some pathology going on unrelated to the Covid infection. There were no healthy controls, including controls who have had Covid-19 but don't have ongoing symptoms.

    About quantitative electromyography:
    Electromyography (EMG) measures muscle response or electrical activity in response to a nerve's stimulation of the muscle.
    Quantitative methods have been developed to characterize MUP waveforms using statistical and probabilistic techniques that allow for greater objectivity and reproducibility in supporting the diagnostic process.

    Muscle weakness and muscle fibre atrophy:
    Could the findings just be a result of deconditioning?

    @Snow Leopard
     
  3. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,520
    Location:
    Aotearoa New Zealand
    Mitochondrial changes
    • Loss of COX activity
    that's Cytochrome oxidase - otherwise known as Complex IV in the mitochondrial respiratory chain (RC). From memory, we haven't seen much about that molecule in ME/CFS. Rather, it was Complex V that was found to not be working properly by the Fisher, Missailidis team.

    • Subsarcolemmal accumulation and/or abnormal cristae
    (note: 'subsarcolemmal' seems to be the correct spelling, just one 'l' in the middle.)
    Subsarcolemmal accumulation: that's an abnormal increase in the number of mitochondria in the cytoplasm adjacent to the muscle cell membrane.
    Cristae are the folded bits inside the mitochondria.

    A 2020 NCNED review: A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
    mentioned that one study had looked at structural abnormalities relating to mitochondria in ME/CFS/SEID patients including sub-sarcolemmal mitochondrial aggregates, among many other things, but did not find any significant structural changes in ME/CFS/SEID patient mitochondria compared with HC participants.
    There's nothing solid on abnormal cristae in ME/CFS in that 2020 review:
     
  4. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    13,269
    Location:
    London, UK
    There is quite an interesting problem here. Almost everyone has had Covid now so anyone presenting with new muscle weakness will be 'post-Covid'. This is presumably a study of patients with enough evidence of muscle disease to deserve a muscle biopsy - the evidence need to be quite good usually. The findings reported in the abstract are not specific and not very dramatic. No detail is given of the electrical findings.

    It would be interesting to see more detail.
     
    merylg, FMMM1, TrixieStix and 11 others like this.
  5. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,520
    Location:
    Aotearoa New Zealand
    Basal lamina
    Yes, 'affected' isn't very specific. It would be good to know how the injuries manifested.

    "The basal lamina is a very thin layer of the extracellular matrix that lies between cells and underlying connective tissue and can be observed under an electron microscope only."

    Screen Shot 2022-06-07 at 8.37.46 pm.png

    "The complex network of the extracellular matrix of basal lamina acts as the scaffold on which cells are anchored. Most cells that have aggregated into tissues have a basal lamina. The basal lamina performs two major functions. It stabilizes the layer of cells attached to it and acts as a barrier to cells that migrate."

    "The components that make up basal lamina are glycoproteins such as laminin, perlecan, entactin, and proteins such as collagen IV. Proteases, enzymes that degrade proteins, such as transforming growth factor-beta, insulin-like growth factor, and fibroblast growth factor may also be present in the basal lamina. ... [the laminin sheet] is connected to the cells by the protein integrin, which anchors the cells to the laminin sheet"


    There's this 2021 study by Germain and Hanson that mentions the extracellular matrix in relation to ME/CFS:
    In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling
    The basal lamina is part of the extracellular matrix.

    That's two proteins out of the 9 proteins highlighted as most significantly different between controls and ME/CFS, both were upregulated. And that's 9 proteins out of 4979 tested.

    Screen Shot 2022-06-07 at 9.01.56 pm.png
    Pathway descriptions fitting the altered levels of proteins related to immunity and
     
    merylg, FMMM1, Snow Leopard and 4 others like this.
  6. FMMM1

    FMMM1 Senior Member (Voting Rights)

    Messages:
    2,593
    EDIT - see Hutan's post below this text is inaccurate --- I hadn't read Hutan's post when I wrote it!

    Seems to be separation of test and control groups (plots below). However, as you point out, need to consider if the controls have similar activity levels etc.
    Still interesting though.

     
    Last edited: Jun 10, 2022
  7. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,520
    Location:
    Aotearoa New Zealand
    My question about whether the finding is due to deconditioning relates to the study that is in the first post of this thread i.e. problems found in muscles.

    The chart with the blue and the red relates to the concentrations of two proteins that were reported by Maureen Hansen's team- I posted that because the proteins relate to the issues with the basal lamina that the first study reported.
     
    merylg, FMMM1, Trish and 1 other person like this.
  8. FMMM1

    FMMM1 Senior Member (Voting Rights)

    Messages:
    2,593
    Thank you for the correction.
    So there's a possibility that this is relevant to ME/CFS -
    • population overlap (Nath has stated that in many cases Long Covid looks like ME/CFS & most people have now been infected with Covid);
    • interesting spot re these proteins, I'd pretty much given up on these proteomic studies finding anything
    • so, possibly, might be worth looking at all of this in ME/CFS and maybe combining it with a Long Covid group?
    Pity (muscle biopsy) samples are so difficult to take. Any thoughts re just looking at proteins again (blood samples)?
     
    Hutan and merylg like this.
  9. FMMM1

    FMMM1 Senior Member (Voting Rights)

    Messages:
    2,593
    Hi @Hutan interesting spot re elevated PXDN, and MXRA7, blood plasma levels. Worth contacting Hejbøl, cc Germain & Hanson, to see if they've considered using plasma levels of PXDN and MXRA7 as a biomarker for these basal lamina/extracellular matrix problems?

    Might make this a whole lot more deliverable than biopsies!
     

Share This Page