PDK4 drives time-dependent physical endurance impairment during acute hypoxia by disrupting carbohydrate metabolism

BACKGROUND: Exposure to acute hypoxia severely impairs skeletal muscle function, but the temporal dynamics and underlying mechanisms remain unclear. METHODS: = 11.8%, simulating 4,500 m) for 0, 12, 24, 48, and 72 h. Exercise performance was evaluated through endurance and strength tests. Transcriptomic and metabolic adaptations were detected through RNA-seq and biochemical assays. Target validation was performed using adeno-associated virus (AAV) mediated gene knockdown and dichloroacetate (DCA). RESULTS: Endurance was most severely impaired after 12 h of hypoxic exposure and showed a trend toward recovery by 72 h, whereas muscle strength declined progressively. Hypoxia induced a metabolic reprogramming favoring oxidative phosphorylation, coupled with a marked upregulation of PDK4 at 12 h. This was associated with increased pyruvate dehydrogenase (PDH) phosphorylation, favoring the diversion of pyruvate away from oxidation and contributing to lactate accumulation. Both DCA treatment and AAV-mediated PDK4 knockdown improved endurance performance under hypoxic conditions. CONCLUSION: These findings suggest that acute hypoxia impairs endurance, in part through PDK4-mediated alterations in pyruvate metabolism, providing a mechanistic basis for optimizing nutritional and therapeutic strategies under hypoxic stress.