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

Area of Science:

• Neurology
• Metabolic Disorders
• Immunology

Background:

• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multisystemic illness.
• Pathophysiology remains poorly understood, with skeletal muscle involvement emerging as a key area of research.
• ME/CFS shares similarities with post-viral syndromes like Long COVID.

Purpose of the Study:

• To synthesize historical and pathophysiological findings on ME/CFS.
• To emphasize the role of skeletal muscle in ME/CFS onset and persistence.
• To integrate molecular and cellular evidence into a cohesive framework.

Main Methods:

• Narrative review of literature from 1990-2025.
• Critical integration of clinical, biochemical, and experimental data.
• Focus on oxidative stress, mitochondrial dysfunction, E-C coupling, and muscle secretome in ME/CFS and post-viral syndromes.

Main Results:

• Consistent evidence links ME/CFS skeletal muscle to mitochondrial oxidative stress and redox imbalance.
• Impaired calcium handling and altered signaling pathways are observed in ME/CFS patients' skeletal muscle.
• Historical research shows a shift from psychogenic to biological explanations for ME/CFS.

Conclusions:

• ME/CFS can be viewed as a skeletal muscle-metabolic disorder.
• Oxidative distress, mitochondrial dysfunction, and impaired energy regulation contribute to ME/CFS symptoms.
• Translational research integrating basic and clinical findings is crucial for developing diagnostics and therapies.