Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice.
Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice.
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DOI：
10.3389/fphys.2021.756659
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发表时间：
2021
影响因子：
4
通讯作者：
Gazmuri RJ
中科院分区：
文献类型：
--
作者：
Radhakrishnan J;Baetiong A;Gazmuri RJ
我们之前已经在HEK 293 T细胞和组成性亲环素-D（Cyp-D）敲除（KO）小鼠中报道，Cyp-D消融下调了氧消耗（VO 2），并触发了适应性反应，表现为更高的运动耐力和更少的VO 2。这种适应性反应涉及通过AMPK-TBC 1D 1信号联系向优先利用葡萄糖的代谢转换。我们现在研究了在使用他莫昔芬诱导的ROSA 26-Cre介导的Cyp-D急性消融（即，条件KO，CKO），使他们进行跑步机锻炼，包括五个跑步时段。在第一次跑台跑步时，CKO小鼠和对照组的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）和RER（0.88 ± 0.043 vs. 0.88 ± 0.042）相当。在随后的疗程中，CKO小鼠表现出VO 2更显著的降低（基因型和疗程相互作用p = 0.000），VCO 2降低不太显著，导致RER显著增加（基因型和疗程相互作用p = 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 vs. 4.0 ± 0.9 mg/min，p = 0.003）。CKO小鼠在给定的VO 2下也进行了显著更高的跑步机工作，以功率/VO 2比率表示（7.4 ± 0.2 × 10−3 vs. 6.7 ± 0.2 × 10 −3比率，p = 0.025）。在完成五次跑台跑步后，CKO骨骼肌组织的分析显示AMPK激活增强（0.669 ± 0.06 vs. 0.409 ± 0.11 pAMPK/β-微管蛋白比值，p = 0.005）和TBC 1D 1失活（0.877 ± 0.16对比0.565 ± 0.09 pTBC 1D 1/β-微管蛋白比率，p < 0.05），伴随增加的葡萄糖转运蛋白-4水平，这与AMPK-TBC 1D 1信号传导联系的激活一致，使得葡萄糖利用增加。综上所述，我们的研究表明，与组成性Cyp-D消融一样，急性Cyp-D消融也诱导了O2利用效率增加的状态，为探索使用药理学方法引起相同的反应铺平了道路，这可能在O2限制条件下有益。
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 (VO2) and triggers an adaptive response that manifest in higher exercise endurance with less VO2. 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 VO2 (208.4 ± 17.9 vs. 209.1 ± 16.8 ml/kg min−1), VCO2 (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 VO2 (genotype & session interaction p = 0.000) with less prominent reduction in VCO2 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 VO2 expressed as a power/VO2 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 < 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 O2 utilization efficiency, paving the way for exploring the use of pharmacological approach to elicit the same response, which could be beneficial under O2 limiting conditions.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
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影响因子：
29
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影响因子：
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影响因子：
4.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Lienhard, Gustav E.