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.).
Improved exercise capacity in cyclophilin‐D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake
via
AMPK‐TBC1D1 signaling nexus
