Radhakrishnan Jeejabai, Baetiong Alvin, Gazmuri Raúl J
Resuscitation Institute, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.
Department of Clinical Sciences, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States.
Front Physiol. 2021 Dec 8;12:756659. doi: 10.3389/fphys.2021.756659. eCollection 2021.
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) and triggers an adaptive response that manifest in higher exercise endurance with less VO. This adaptive response involves a metabolic switch toward preferential utilization of glucose 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 (208.4 ± 17.9 vs. 209.1 ± 16.8 ml/kg min), VCO (183.6 ± 17.2 vs. 184.8 ± 16.9 ml/kg min), and RER (0.88 ± 0.043 vs. 0.88 ± 0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO (genotype & session interaction = 0.000) with less prominent reduction in VCO resulting in significantly increased RER (genotype and session interaction = 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, = 0.003). CKO mice also performed a significantly higher treadmill work for given VO expressed as a power/VO ratio (7.4 ± 0.2 × 10 vs. 6.7 ± 0.2 10 ratio, = 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, = 0.005) and TBC1D1 inactivation (0.877 ± 0.16 vs. 0.565 ± 0.09 pTBC1D1/β-tubulin ratio, < 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 utilization efficiency, paving the way for exploring the use of pharmacological approach to elicit the same response, which could be beneficial under O limiting conditions.
我们之前在人胚肾293T细胞和组成型亲环蛋白D（Cyp-D）基因敲除（KO）小鼠中报道，Cyp-D缺失会下调氧消耗（VO）并触发一种适应性反应，表现为更高的运动耐力和更低的VO。这种适应性反应涉及代谢转向优先利用葡萄糖的AMPK-TBC1D1信号通路。我们现在研究了在使用他莫昔芬诱导的ROSA26-Cre介导的（即条件性敲除，CKO）急性敲除Cyp-D的小鼠中，通过让它们进行包括五个跑步阶段的跑步机运动，是否能触发类似的反应。在第一次跑步机跑步阶段，CKO小鼠和对照组的VO（208.4±17.9对209.1±16.8毫升/千克·分钟）、VCO（183.6±17.2对184.8±16.9毫升/千克·分钟）和呼吸交换率（RER）（0.88±0.043对0.88±0.042）相当。在随后的阶段，CKO小鼠的VO下降更为显著（基因型与阶段交互作用=0.000），而VCO下降不那么显著，导致RER显著增加（基因型和阶段交互作用=0.013）。RER的增加与优先利用葡萄糖作为呼吸底物一致（4.6±0.8对4.0±0.9毫克/分钟，=0.003）。对于给定的VO，CKO小鼠以功率/VO比值表示的跑步机工作量也显著更高（7.4±0.2×10对6.7±0.2 10比值，=0.025）。在完成五个跑步机跑步阶段后，对CKO骨骼肌组织的分析显示，AMPK激活增强（0.669±0.06对0.409±0.11 pAMPK/β-微管蛋白比值，=0.005）和TBC1D1失活（0.877±0.16对0.565±
