Metabolic adaptation and fragility in healthy 3D<i>in vitro</i>skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera.

Evidence Atlas

Metabolic adaptation and fragility in healthy 3Din vitroskeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera.

Mughal, Sheeza, Andújar-Sánchez, Félix, Sabater-Arcis, Maria et al. · Biofabrication · 2025 · DOI

Quick Summary

Researchers grew human muscle tissue in the laboratory and exposed it to blood from ME/CFS and Long COVID patients to see what happens. They found that muscle exposed to patient blood initially tries to work harder by burning more fuel, but over time the muscle becomes weak and fragile. The mitochondria (the energy-producing structures in cells) also change shape and stop working properly, suggesting the muscle is struggling under stress.

Why It Matters

This is the first laboratory model demonstrating how ME/CFS patient blood may directly damage skeletal muscle tissue, potentially explaining the muscle weakness and post-exertional malaise many patients experience. Understanding this mechanism could lead to new diagnostic tests and targeted treatments for muscle dysfunction in ME/CFS and Long COVID. The findings suggest that the problem originates in circulating blood factors rather than the muscle itself, opening new therapeutic avenues.

Observed Findings

Short-term serum exposure (48 hours) significantly reduced muscle contractile strength in engineered tissues.
Muscle tissues showed upregulation of glycolytic enzymes and increased mitochondrial oxygen consumption, indicating a hypermetabolic state.
Prolonged serum exposure (96-144 hours) led to muscle fragility, weakness, and mitochondrial fragmentation into abnormal toroidal shapes.
Transcriptomic analysis revealed disturbances in calcium homeostasis and increased protein translation in response to patient sera.
Muscle fibers (myotubes) showed evidence of hypertrophy alongside mitochondrial dysfunction.

Inferred Conclusions

Skeletal muscle in ME/CFS progresses through a time-dependent metabolic adaptation, initially increasing glycolysis as a compensatory mechanism but eventually deteriorating under prolonged stress.
Circulating factors in ME/CFS and Long COVID patient sera directly impair muscle function and mitochondrial integrity in ways that can be modeled in vitro.
The shift from mitochondrial hyperfusion to fragmentation represents a critical transition from adaptive response to cellular failure.
Mitochondrial dysfunction and energy metabolism dysregulation may be central to muscle weakness and fatigue in these conditions.

Remaining Questions

What This Study Does Not Prove

This study does not prove that the factors in patient sera are the sole cause of ME/CFS muscle symptoms in actual patients, nor does it identify which specific blood components are responsible for the damage. The in vitro model, while valuable, does not fully replicate the complex biological environment of the human body, so these findings require confirmation in patient studies. Correlation between serum exposure and muscle changes does not establish causation in the living organism.

Metadata

DOI: 10.1088/1758-5090/adf66c
PMID: 40744071
Review status: Machine draft
Evidence level: Early hypothesis, preprint, editorial, or weak support
Last updated: 8 April 2026