Constitutive cyclophilin-D ablation in mice increases exercise and cognitive-behavioral performance under normoxic and hypoxic conditions

We recently reported that constitutive ablation of cyclophilin-D (Cyp-D) in mice reduces oxygen consumption (VO₂) while paradoxically increasing exercise endurance, thereby demonstrating increased O₂ utilization efficiency. This response was associated with augmented glucose uptake and glucose utilization, in part mediated through adenosine monophosphate-activated kinase signaling. We now hypothesized that Cyp-D knock-out (KO) mice might also exhibit improved cognitive-behavioral performance and that these favorable adaptive responses may persist under hypoxic conditions. We therefore assessed under normoxic (20.9% O₂, simulating ground O₂ levels) and hypoxic (8% O₂, simulating 7600 m altitude O₂ levels) conditions exercise capacity and cognitive-behavioral performance. We used a treadmill test to assess exercise capacity, a pole-test to assess agility, an elevated-plus-maze test to assess anti-anxiety, and a passive avoidance test to assess learning and memory retention. Compared to wild type, Cyp-D KO mice showed comparable treadmill work under normoxia (48 ± 12 vs 47 ± 9 Joules) but increased treadmill work (12 ± 1 vs 8 ± 1 Joules; p = 0.02) under hypoxia. Cyp-D KO mice displayed increased pole-descending time (17 ± 3 vs 8 ± 2 s; p ≤ 0.05) under normoxia but shorter pole-descending time (21 ± 3 vs 37 ± 4 s; p ≤ 0.01) under hypoxia. In addition, the Cyp-D KO mice demonstrated increased elevated plus-maze open arm time (91 ± 31 vs 23 ± 12 s; p ≤ 0.05) under hypoxia and increased latency to enter dark chamber (261 ± 23 vs 185 ± 42 s; p ≤ 0.05) under normoxia. Thus, our experiments showed that under normoxia Cyp-D KO mice displayed anti-anxiety behavior and improved learning and memory retention. Under hypoxia, Cyp-D KO mice displayed increased exercise capacity, increased agility, and increased anti-anxiety consistent with our previously reported findings of increased O₂ utilization efficiency. Identifying interventions to elicit these effects could be beneficial in a myriad of physiological and clinical conditions in which increasing O₂ utilization efficiency would be advantageous.