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We have previously reported in HEK 293 T cells and in constitutive cyclophilin-D (Cyp-D) knockout (KO) mice that Cyp-D ablation downregulates oxygen consumption (VO 2 ) and triggers an adaptive response that manifest in higher exercise endurance with less VO 2 . This adaptive response involves a metabolic switch toward preferential utilization of glucose  via  AMPK-TBC1D1 signaling nexus. We now investigated whether a similar response could be triggered in mice after acute ablation of Cyp-D using tamoxifen-induced ROSA26-Cre-mediated (i.e., conditional KO, CKO) by subjecting them to treadmill exercise involving five running sessions. At their first treadmill running session, CKO mice and controls had comparable VO 2  (208.4 ± 17.9 vs. 209.1 ± 16.8 ml/kg min −1 ), VCO 2  (183.6 ± 17.2 vs. 184.8 ± 16.9 ml/kg min −1 ), and RER (0.88 ± 0.043 vs. 0.88 ± 0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO 2  (genotype &amp;amp; session interaction  p  = 0.000) with less prominent reduction in VCO 2  resulting in significantly increased RER (genotype and session interaction  p  = 0.013). The increase in RER was consistent with preferential utilization of glucose as respiratory substrate (4.6 ± 0.8 vs. 4.0 ± 0.9 mg/min,  p  = 0.003). CKO mice also performed a significantly higher treadmill work for given VO 2  expressed as a power/VO 2  ratio (7.4 ± 0.2 × 10 −3  vs. 6.7 ± 0.2 10 −3  ratio,  p  = 0.025). Analysis of CKO skeletal muscle tissue after completion of five treadmill running sessions showed enhanced AMPK activation (0.669 ± 0.06 vs. 0.409 ± 0.11 pAMPK/β-tubulin ratio,  p  = 0.005) and TBC1D1 inactivation (0.877 ± 0.16 vs. 0.565 ± 0.09 pTBC1D1/β-tubulin ratio,  p  &amp;lt; 0.05) accompanied by increased glucose transporter-4 levels consistent with activation of the AMPK-TBC1D1 signaling nexus enabling increased glucose utilization. Taken together, our study demonstrates that like constitutive Cyp-D ablation, acute Cyp-D ablation also induces a state of increased O 2  utilization efficiency, paving the way for exploring the use of pharmacological approach to elicit the same response, which could be beneficial under O 2  limiting conditions.

Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice