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

We previously reported in HEK 293T cells that silencing the mitochondrial peptidyl prolyl isomerase cyclophilin-D (Cyp-D) reduces o. We now report that Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduces o both at rest (∼15%) and during treadmill exercise (∼12%). Yet, despite o reduction, these Cyp-D KO mice ran longer (1071 ± 77 785 ± 79 m; = 0.002), for longer time (43 ± 3 34 ± 3 min; = 0.004), and at higher speed (34 ± 1 29 ± 1 m/s; ≤ 0.001), resulting in increased work (87 ± 6 58 ± 6 J; ≤ 0.001). There were parallel reductions in carbon dioxide production, but of lesser magnitude, yielding a 2.3% increase in the respiratory exchange ratio consistent with increased glucose utilization as respiratory substrate. In addition, primary skeletal muscle cells of Cyp-D KO mice subjected to electrical stimulation exhibited higher glucose uptake (4.4 ± 0.55 2.6 ± 0.04 pmol/mg/min; ≤ 0.001) with enhanced AMPK activation (0.58 ± 0.06 0.38 ± 0.03 pAMPK/β-tubulin ratio; ≤ 0.01) and TBC1 (Tre-2/USP6, BUB2, Cdc16) domain family, member 1 (TBC1D1) inactivation. Likewise, pharmacological activation of AMPK also increased glucose uptake (3.2 ± 0.3 2.3 ± 0.2 pmol/mg/min; ≤ 0.001). Moreover, lactate and ATP levels were increased in these cells. Taken together, Cyp-D ablation triggered an adaptive response resulting in increased exercise capacity despite less oxygen utilization associated with increased glucose uptake and utilization involving AMPK-TBC1D1 signaling nexus.-Radhakrishnan, J., Baetiong, A., Kaufman, H., Huynh, M., Leschinsky, A., Fresquez, A., White, C., DiMario, J. X., Gazmuri, R. J. Improved exercise capacity in cyclophilin-D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake AMPK-TBC1D1 signaling nexus.