Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement, 2026, Fanò-Illic

Dolphin

Dolphin

Senior Member (Voting Rights)

Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement​

by
Giorgio Fanò-Illic
1,2,3,4<i></i>,
Francesco Coscia
3,5<i></i>,
Paola V. Gigliotti
3,5<i></i>,
Franco Checcaglini
3<i></i>,
Ugo Carraro
4,6<i></i>,
Stefania Fulle
1,2<i></i> and
Rosa Mancinelli
1,2,*<i></i>



1
Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
2
IIM—Interuniversity Institute of Myology, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
3
Campus of Free University of Alcatraz, Free University of Alcatraz, Santa Cristina di Gubbio, 06024 Gubbio, Italy
4
A&C M-C Foundation for Translational Myology, 35100 Padova, Italy
5
Sports Medicine Service of the San Candido, Innichen and Brunico-Bruneck Hospitals, Bolzano-Bozen, 39038 San Candido, Italy
6
Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy
*
Author to whom correspondence should be addressed.
Diagnostics 2026, 16(7), 1019; https://doi.org/10.3390/diagnostics16071019
Submission received: 11 February 2026 /Revised: 13 March 2026 / Accepted: 26 March 2026 /Published: 28 March 2026
(This article belongs to the Special Issue New Trends in Mobility Medicine Diagnostics)
Download keyboard_arrow_down
Browse Figures
Versions Notes



Abstract​

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances.

Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention.

This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework.

This is a narrative review of published literature (1990–2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation–Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID).

Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca2+ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS.

Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings.

ME/CFS can be interpreted as a skeletal muscle–metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise.

Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers.

Keywords:
oxidative stress; skeletal muscle; mitochondria; chronic fatigue; post-exertional malaise; Long COVID; E-C coupling dysregulation; redox imbalance; pacing
 
Dolphin said:
Evidence consistently points to mitochondrial oxidative stress
Click to expand...
nope
Dolphin said:
ME/CFS can be interpreted as a skeletal muscle–metabolic disorder characterized by oxidative distress, mitochondrial dysfunction
Click to expand...
nope

Almost all of the mitochondrial studies cited can be wholesale dismissed on methodological or interpretation flaws, nor do they even consistently show these things if that were not the case, nor are they comparable to each other because of sample types, techniques used, cohorts selected

Honestly at this point I am considering writing a mitochondrial mythbusting literature review but I suspect it's just going to get ignored and complained about by the people repeating these memes
 
Last edited:
NelliePledge said:
it would be on record though which is important.
Click to expand...
I agree.

I think the record needs to be set straight regarding what are reliable clues, what are long shots and what are demonstrable dead ends. We need to focus effort and resources on priority areas indicated either by evidence or by specific events not yet explored that can plausibly lead to symptoms (also in specific terms of time course, etc). The issue as ever is that specifics are either absent or don’t withstand close scrutiny.

It’s not that mitochondria are definitely not relevant. Far from it. The issue is that everything gets muddled together nonspecifically when the m word appears, and when specifics do arise they tend to be things that to my mind don’t fit the clinical picture or are not supported by consistent evidence (or both). Like sweeping statements about energy production and fatigue that do not capture the relevant nuances of either. I say this from experience, to my own detriment, given components of my early work or presentations that i have publicly given that make the same mistakes.

I think mitochondrial turnover and relationships with broader signalling pathways affecting the brain and the immune system are the most plausible issues, while being under-studied in this disease context and also supported by current evidence as far as I understand things like DecodeME and recently emerging work on circulating cell-free mtDNA. The greatest advantage to looking into this is that much of the relevant biology is already well understood.

I’ll see if I can somehow squeeze writing something like this into my already overloaded schedule. Parts of the argument would be greatly strengthened by a forthcoming paper from our lab as well as two about to finish PhDs. Perhaps following these would be good timing for something like this.

I hate releasing preprints because of confusion around citations or potential propagation of errors, but I do want to get this right so I may invite members here to take part if this does eventuate. I know there are people here whose hypotheses are along similar lines or who have undertaken very rigorous experimental work in similarly trying to narrow down useful angles.

Sorry if there’s redundancy in the writing of this post, it’s an impassioned bout of 1:00am delirium from a tiny phone screen, and it’s a manifestation of years of brow-crinkled thoughts had in the quiet and solitary moments of daily carpark strolls, and so on.
 
Last edited:
You must log in or register to reply here.
Back
Top Bottom