Trial Report Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19, 2024, Mughal

https://www.sciencedirect.com/science/article/abs/pii/S0960896624003353

571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19
Author links
1
Institute For Bioengineering Of Catalonia BIST, Barcelona, Spain
2
ICREA Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
3
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
4
Universitat de Barcelona, Barcelona, Spain
Available online 4 October 2024, Version of Record 4 October 2024.


https://doi.org/10.1016/j.nmd.2024.07.171Get rights and content

Myalgic encephalomyelities/ chronic fatigue syndrome and long COVID-19 are clinically challenging, multi-symptomatic conditions with multiple overlapping symptoms.

Unfortunately, contemporary research is directly being done on patients which risks exacerbating their symptoms.

Using our 3-D in vitro skeletal muscle tissues we have mapped the progression of functional, physiological, and metabolic adaptations of the tissues in response to patient sera over time.

During short exposure we treated the tissues for 48 hours with patient sera.

The contractile profiles of these tissues were severely compromised.

Transcriptomic analyses of these short exposure samples showed an absence of significant differentially expressed genes between ME/CFS and LC-19.

The analyses revealed an upregulation of glycolytic enzymes especially of PDK4, suggesting a switch away from Oxidative Phosphorylation as well as a decline in DRP1, involved in mitochondrial fission.

Subsequent structural analyses confirmed hypertrophy in myotubes and hyperfused mitochondrial networks.

Mitochondrial oxygen consumption capacity, evaluated through the MitoStress test, was also elevated, as was the non-mitochondrial respiration confirming the shift to glycolysis.

Interestingly, at short exposures of 48 hours, the muscle tissues appeared to be adapting to the stress factors by upregulating glycolysis and increasing the muscular metabolic volume.

Prolonging the exposure to 96 and 144 hours induced high fatiguability, and fragility in tissues.

The mitochondria, at longer exposures, appeared to be fragmented and assumed a toroidal conformation indicating a change in mitochondrial membrane potential.

We hypothesize that the disease progresses through an intermediary stress-induced hypermetabolic state, ultimately leading to severe deterioration of muscle function.

This is the first account of research that proposes acquired metabolic plasticity in 3D skeletal muscles exposed to ME/CFS and Long COVID-19 sera.

S. Mughal, F. Andújar-Sánchez, M. Sabater-Arcis, J. Fernández-Costa, J. Ramón-Azcón,
571P Muscular metabolic plasticity in 3D in vitro models against systemic stress factors in ME/CFS and long COVID-19,
Neuromuscular Disorders,
Volume 43, Supplement 1,
2024,
104441.162,

 

Wow! This seems significant to me, exhibiting the effects of patient serum on muscle tissue just in a matter of days. Thanks for posting @Dolphin

There is suggestion of the PDK4-SEPT2-DRP1 axis implicated in neurodegenerative diseases and ER stress, but in context with above study in muscle tissue there is also relevance to sarcopenia exhibited in this study:
The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4

Observe sarcopenia can be a consequence of cancer cachexia, malabsorption, and sepsis / infection.

Why might mitochondria fragment one might ask?

Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone

 

Is this a PEM model? we need so desperately to have a benchtop model in this disease. Working on people is so slow, expensive and variable. I didn't see this coming but I am excited by it.

To be fair, "3-d in vitro skeletal muscle tissues" don't sound super cheap and easy to get! but they have to be more malleable than whole people...

 

There's a 2023 paper here that talks about the history and process behind "3D muscle models".

Muscle-on-a-chip devices: a new era for in vitro modelling of muscular dystrophies
Juan M. Fernández-Costa,1 Ainoa Tejedera-Vilafranca,1 Xiomara Fernández-Garibay,1 and Javier Ramón-Azcón1,2,*

ABSTRACT
Muscular dystrophies are a heterogeneous group of highly debilitating diseases that result in muscle atrophy and weakness. The lack of suitable cellular and animal models that reproduce specific aspects of their pathophysiology is one of the reasons why there are no curative treatments for these disorders. This highlights a considerable gap between current laboratory models and clinical practice. We strongly believe that organs-on-chip could help to fill this gap. Organs-on-chip, and in particular muscles-on-chip, are microfluidic devices that integrate functional skeletal muscle tissues. Biosensors in these systems allow monitoring of muscle homeostasis or drug responses in situ. This Perspective outlines the potential of organs-on-chip as advanced models for muscular dystrophies, as well as the current challenges and future opportunities for this technology.


The models are still new but the research group seems to have deployed the models in several conditions. It is this week presenting several posters on research using the 3d muscle model:



One last thought: subtyping. If you have 100 standard muscle models and put serum from 100 mecfs patients on them and measure what happens, you might be able to subtype in a practical way.

 

This is amazing work! Brilliant idea to use 3D-printed muscle tissue. (Edit: not 3D-printed, but still a brilliant idea to use 3D.)

Hasn’t Bhupesh Prusty talked about exactly this? About DRP1 and fragmented mitochondria? For instance, here: https://www.sciencedaily.com/releases/2022/05/220504110408.htm

In the lecture posted below, Prusty is talking about a collaboration with someone in Barcelona. Might it be the same team as those who did this research or another one?

“2:08:18 Just to conclude, the last slide. We have started working on muscle level also, taking this IgG biobank that we have created and we are putting it onto an organ-on-a-chip model, so, the tiny muscles on a small chip and we are putting this IgG into the muscles and trying to see what type of dysfunctions are happening in the muscles at all the levels and all the things.

2:08:46 This is an ongoing collaboration with Dr Carles Rentero from Barcelona.”

https://docs.google.com/document/d/1T79bGDR1w31zHhS39AXz3wDyhlmvwadg/mobilebasic

 

This is an abstract for a poster presentation at a meeting, rather than a full paper.
There is no mention of any controls.
I think we need more information to assess this.

 

Sorry, I misunderstood their words “3-D in vitro skeletal muscle” and “3D skeletal muscles exposed to ME/CFS and Long COVID-19 sera.”

 

My read of their other papers suggests the distinction is not that it is 3D printed, but that other researchers are using 2d layers of muscle cells, which don't fully capture the behaviour of muscles in certain conditions. They have these little slivers of 3d muscle and they seem to be able to model the muscular dystrophies better with them.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10309590/

We;ve seen researchers soak cells in patient serum before, the difference here is that the muscle behaviour is likely more lifelike. I've emailed the first author to get the full poster, we can see what further details are in there.

 

Thanks @Murph for the explanation! Will be interesting to see further details!

 

SHe replies:
Glad to hear from you and thank you for your interest in the work (not a lot of it in this space, as you perhaps already know). Unfortunately, this is an abstract of the research I am presenting at a conference. The manuscript itself is submitted to a journal and we are waiting to hear back from them. As soon as it is published, I will share it with you.

 

It does sound interesting and a few other studies pop into my mind when reading the abstract. (Those that looked at membrane potential and the electrical properties of cells, muscle function and grip strength, etc).

But as @Jonathan Edwards mentions there really is such scant information I find it difficult to get too excited. Looking forward to hearing more though. And thanks @Murph for reaching to try to get more detail.