Metabolic dysregulation in PAC(V)S — three therapeutic axes

Gracidas C, Levy R, Varon J, Halma MTJ. Lactate, Capnia, and Fat Oxidation as therapeutic axes for SARS-CoV-2 spike protein-induced sequelae. Hormone and Metabolic Research (submitted Nov 2025). Manuscript ID HMR-2025-11-0497.

Axis 1 — impaired beta-oxidation
Fatty acids cannot be burned efficiently → cells default to glycolysis → premature lactate accumulation
Symptom-level
  • Exercise intolerance
  • PEM at low exertion
  • Rapid muscle fatigue
  • Metabolic inflexibility
  • Normal spirometry and cardiac function
Lab evidence
  • ↓ Fat oxidation rate at CPET [16, 50]
  • ↑ Acylcarnitines in plasma [51]
  • ↓ C2/C3 short-chain acylcarnitines [53, 54]
  • ↓ OXPHOS enzymes PDHB, DLST, ACADM [multi-omics]
  • ↑ Glycolytic enzymes HK2, GAPDH, PGK1
  • Disrupted mitochondria on muscle biopsy [9, 10]
Mechanism
  • Spike → SREBP/DGAT1 → lipid droplet diversion [70]
  • ORF9b → TOM70 inhibition → impaired mitochondrial protein import [71]
  • ↓ TOM20 expression [77]
  • Malonyl-CoA → CPT-1 inhibition → ↓ fatty acid entry to mitochondria [5]
  • NLRP3/NF-κB cytokines further impair respiration [23–26]
Axis 2 — capnia dysregulation (hypocapnia)
Chronic low CO₂ impairs oxygen unloading via leftward oxyhemoglobin curve shift → tissue hypoxia and cerebral vasoconstriction
Symptom-level
  • Breathlessness with normal O₂ saturation
  • Brain fog / cognitive impairment
  • Dizziness, orthostatic intolerance
  • Dyspnea with normal PFTs
  • Sighing, yawning, sensation of air hunger
Lab evidence
  • ↓ PETCO₂ with normal respiratory rate [62]
  • Delayed PETCO₂ recovery on HVPT — all 6/6 patients [Ritter 2024]
  • Persisting ventilatory inefficiency at 34 months [59]
  • Acute/compensated respiratory alkalosis in 14 patients [119]
  • Sensitised carotid chemoreflex [95]
  • ↑ intrapulmonary shunt 37%, ↑ alveolar dead space 86% [92]
Mechanism
  • GPCR autoantibodies → autonomic dysf. → compensatory hyperventilation
  • ↓ CO₂ → leftward oxyhemoglobin curve shift → impaired O₂ release
  • Endothelial dysfunction → ↑ vWF, Factor VIII, thrombomodulin [90]
  • Sensitised carotid chemoreflex amplifies ventilatory drive [95]
  • ↑ alveolar dead space compounds inefficiency [92]
Axis 3 — elevated lactate / reduced lactate threshold
Anaerobic metabolism activated at minimal exertion → early acidosis, muscle pain, and PEM
Symptom-level
  • Muscle burning at low workloads
  • Fatigue after minimal activity
  • PEM triggered by normal exertion
  • Reduced anaerobic threshold on CPET
  • Muscle pain and myalgia
Lab evidence
  • ↑ blood lactate at low workload CPET [16, 18]
  • Elevated resting lactate correlates with PEM severity [21]
  • ↑ lactate/pyruvate ratio at rest [57]
  • ↑ LDH in PASC [58]
  • Abnormal lactate accumulation in ME/CFS on 2-day CPET [22]
  • ↑ F2-isoprostanes, malondialdehyde [48]
Mechanism
  • Mitochondrial damage → shift to glycolysis → premature lactate
  • Nsp6 → MGA/MAX → glycolytic switch in cardiomyocytes [27]
  • NLRP3 / NF-κB cytokines further impair respiration [26]
  • ↓ peripheral O₂ extraction from microvascular dysfunction [87, 88]
  • Impaired lactate clearance capacity [20]
All three axes are interdependent and converge on the same triad: fatigue · post-exertional malaise · brain fog.
Axis 1 and 3 are mechanistically coupled (impaired β-oxidation forces glycolysis → lactate). Axis 2 amplifies both by impairing O₂ delivery to already metabolically stressed tissue.
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