Increased exercise tolerance in humanized G6PD-deficient mice.

Area of Science:

• Biochemistry
• Exercise Physiology
• Genetics

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency impacts 500 million globally, compromising red blood cell antioxidant defenses and increasing hemolysis risk under oxidative stress.
• The effects of exercise, a known generator of reactive oxygen species, on G6PD deficiency remain largely uncharacterized.

Purpose of the Study:

• To investigate exercise performance and molecular adaptations in a humanized mouse model of G6PD deficiency (Mediterranean variant, S188F) with 10% enzymatic activity.

Main Methods:

• Utilized humanized mouse models expressing a G6PD Mediterranean variant (S188F) and control mice.
• Assessed exercise performance (critical speed), red blood cell morphology, hemolysis, cardiac function, and cardiac/skeletal muscle molecular profiles (proteomics, metabolomics) post-exercise.

Main Results:

• G6PD-deficient mice exhibited superior critical speed compared to controls.
• No differences in red blood cell morphology or hemolysis were observed post-exercise.
• Deficient mice showed enhanced cardiac function (cardiac output, stroke volume, sarcomere length) and increased mitochondrial content.
• Proteomics and metabolomics revealed improved mitochondrial function, increased protein turnover, altered energy metabolism, and enhanced fatty acid oxidation in G6PD-deficient muscles.

Conclusions:

• G6PD deficiency, particularly with noncanonical variants, may confer a metabolic advantage for exercise performance.
• Findings challenge the presumed universal hemolytic risk during exercise in G6PD deficiency.
• Exercise may induce beneficial cardiac and metabolic adaptations in G6PD-deficient individuals.