Glycerol 3-phosphate dehydrogenase 1 deficiency enhances exercise capacity due to increased lipid oxidation during...

A large percentage of energy produced during high-intensity exercise depends on the aerobic glycolytic pathway. Maintenance of a cytoplasmic redox balance ([NADH]/[NAD(+)] ratio) by the glycerophosphate shuttle involves sustained aerobic glycolysis. Glycerol 3-phosphate dehydrogenase 1 (GPD1) catalyzes an oxidation reaction in the glycerophosphate shuttle. In this study, we examined whether GPD1 deficiency decreases exercise capacity due to impairment of aerobic glycolysis by using the GPD1 null mouse model BALB/cHeA (HeA). Unexpectedly, we found that exercise endurance was significantly higher in HeA mice than in BALBc/By (By) mice used as controls. Furthermore, aerobic glycolysis in HeA mice was not impaired. During exercise, lipid oxidation was significantly higher in HeA mice than in By mice, concomitant with an increase in phosphorylation of AMP-activated protein kinase (AMPK). HeA mice also showed a delay in the onset of muscle glycogen usage and lactate production during exercise. These data suggest that contribution of lipid oxidation as a fuel source for exercise is increased in HeA mice, and GPD1 deficiency enhances exercise capacity by increasing lipid oxidation, probably due to activation of AMPK. We propose that GPD1 deficiency induces an adaptation that enhances lipid availability in the skeletal muscle during exercise.