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

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, noin vitromodel exists to study skeletal muscle wasting, peripheral weakness, or potential therapies. We developed 3Din vitroskeletal muscle tissues to map muscle adaptations to patient sera over time. Short exposures (48 H) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of protein translation, glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption In ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96-144 H) caused muscle fragility and weakness, with mitochondria fragmenting into a toroidal conformation. We propose that skeletal muscle tissue in ME/CFS and LC-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation.