Gut-confined fullerene reprograms lactate metabolism to Rescue hypoxia-induced exercise intolerance

Area of Science:

• Biomedical Science
• Physiology
• Gastroenterology

Background:

• Chronic hypoxia causes exercise intolerance, a key feature of high-altitude deterioration (HADT).
• Current therapies for HADT lack long-term safety and efficacy.
• Targeting gut-specific mechanisms offers a novel therapeutic avenue.

Purpose of the Study:

• To develop and evaluate an orally administered fullerene (C60) suspension for treating chronic hypoxia-induced exercise intolerance.
• To investigate the mechanism of action of fullerene in the gastrointestinal tract.
• To assess the safety and efficacy of fullerene for HADT.

Main Methods:

• Development of an orally administered fullerene (C60) suspension with negligible systemic absorption.
• Administration of fullerene to subjects under chronic hypoxia conditions.
• Assessment of systemic lactate levels, exercise endurance, gut lactate metabolism, reactive oxygen species (ROS) levels, hypoxia-inducible factor-1α (HIF-1α) stability, glycolysis, intestinal barrier integrity, and hypoxia-induced gut damage.

Main Results:

• Fullerene significantly reduced systemic lactate and enhanced exercise endurance in chronic hypoxia.
• Fullerene acted locally in the gut, quenching ROS in intestinal epithelial cells and destabilizing HIF-1α.
• This led to suppressed gut glycolysis, reduced endogenous gut lactate production, and preserved intestinal barrier integrity.
• No significant effects on muscle, hepatic, or renal lactate metabolism were observed.

Conclusions:

• Orally administered fullerene (C60) provides a safe and effective "local-to-systemic" therapeutic strategy for HADT by targeting gut-derived lactate.
• This approach mitigates hypoxia-induced exercise intolerance and gut damage with minimal systemic exposure.
• Fullerene presents a promising therapeutic for HADT and potentially other hypoxia-associated diseases.