Abstract 176: Genetic Ablation of Cyclophilin-D in Mice Increases Physical and Cognitive Performance During Hypoxia

Abstract

Introduction: We previously reported that silencing of the mitochondrial peptidyl-prolyl isomerase Cyclophilin-D (Cyp-D) in HEK 293T cells reduces oxygen consumption (VO 2 ). In vivo Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduced VO 2 while paradoxically increased exercise endurance, thus demonstrating increased oxygen utilization efficiency. Therefore, we hypothesized that Cyp-D KO mice will display improved physical and cognitive performance during hypoxic conditions. Methods: Two groups of 9 mice each, age and gender-matched, representing wild-type (WT) and Cyp-D KO were subjected to treadmill running first under normobaric normoxic conditions (20.9% O 2 , simulating ground level O 2 levels), and the next day under normobaric hypoxic conditions (8% O 2 simulating 7,600 meters altitude O 2 levels). Total running time and distance, V max , and work performed were measured. A separate set of 9 mice each (Cyp-D KO and WT), were subjected to behavioral assessments; a pole test to assess motor function and an elevated plus-maze test to assess anxiety levels. The tests were conducted first under normoxia and then under hypoxia. Results: Cyp-D KO mice exposed to 8% O 2 displayed increased treadmill work (12±1 vs 8±1 Joules; p =0.02) demonstrating increased exercise capacity, shorter pole-climbing time (21±3 vs 37±4 sec; p =0.006) demonstrating increased agility and cognitive function, and increased elevated plus-maze open arm time (91±31 vs 23±12 sec; p =0.046) demonstrating anti-anxiety like behavior. Conclusions: Cyp-D KO mice demonstrated increased exercise capacity, improved motor function, decreased anxiety, and improved cognitive function under hypoxia. Thus, targeting Cyp-D and modulating its activity may impact several acute and chronic conditions in which oxygen availability is limited. The increased cognitive performance could be helpful when working at low environmental O 2 levels (e.g., high-altitude, underground caves, etc.).