| First Author | Radhakrishnan J | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 10 | Pages | 11443-11457 |
| PubMed ID | 31339770 | Mgi Jnum | J:293569 |
| Mgi Id | MGI:6452992 | Doi | 10.1096/fj.201802238R |
| Citation | Radhakrishnan J, et al. (2019) Improved exercise capacity in cyclophilin-D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake via AMPK-TBC1D1 signaling nexus. FASEB J 33(10):11443-11457 |
| abstractText | We previously reported in HEK 293T cells that silencing the mitochondrial peptidyl prolyl isomerase cyclophilin-D (Cyp-D) reduces Vo2. We now report that in vivo Cyp-D ablation using constitutive Cyp-D knockout (KO) mice also reduces Vo2 both at rest ( approximately 15%) and during treadmill exercise ( approximately 12%). Yet, despite Vo2 reduction, these Cyp-D KO mice ran longer (1071 +/- 77 vs. 785 +/- 79 m; P = 0.002), for longer time (43 +/- 3 vs. 34 +/- 3 min; P = 0.004), and at higher speed (34 +/- 1 vs. 29 +/- 1 m/s; P </= 0.001), resulting in increased work (87 +/- 6 vs. 58 +/- 6 J; P </= 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 vs. 2.6 +/- 0.04 pmol/mg/min; P </= 0.001) with enhanced AMPK activation (0.58 +/- 0.06 vs. 0.38 +/- 0.03 pAMPK/beta-tubulin ratio; P </= 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 vs. 2.3 +/- 0.2 pmol/mg/min; P </= 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 via AMPK-TBC1D1 signaling nexus. |
