Premium
Improved exercise capacity in cyclophilin‐D knockout mice associated with enhanced oxygen utilization efficiency and augmented glucose uptake via AMPK‐TBC1D1 signaling nexus
Author(s) -
Radhakrishnan Jeejabai,
Baetiong Alvin,
Kaufman Harrison,
Huynh Michelle,
Leschinsky Angela,
Fresquez Adriana,
White Carl,
DiMario Joseph X.,
Gazmuri Raúl J.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802238r
Subject(s) - ampk , nexus (standard) , knockout mouse , chemistry , microbiology and biotechnology , medicine , endocrinology , protein kinase a , biology , biochemistry , computer science , receptor , kinase , embedded system
We previously reported in HEK 293T cells that silencing the mitochondrial peptidyl prolyl isomerase cyclophilin‐D (Cyp‐D) reduces V o 2 . We now report that in vivo Cyp‐D ablation using constitutive Cyp‐D knockout (KO) mice also reduces V o 2 both at rest (∼15%) and during treadmill exercise (∼12%). Yet, despite V o 2 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/β‐tubulin ratio; P ≤ 0.01) and TBC1 (Tre‐2/USP6, BUB2, Cdcl6) 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. FASEB J. 33, 11443–11457 (2019). www.fasebj.org