Department of Biology, University of Copenhagen, Denmark.
Department of Biology, University of Copenhagen, Denmark.
Exp Gerontol. 2017 Nov;98:124-133. doi: 10.1016/j.exger.2017.08.006. Epub 2017 Aug 8.
Aging is associated with changes in several metabolic pathways affecting liver function including the adaptive unfolded protein response (UPR). On the other hand, exercise training has been shown to exert beneficial effects on metabolism in the liver and exercise training has been reported to affect hepatic UPR. PGC-1α is a transcriptional coactivator involved in exercise training-induced adaptations in skeletal muscle and liver. Therefore, the aim of the present study was to examine the impact of PGC-1α in aging and lifelong exercise training-induced hepatic UPR in mice. Liver was obtained from young (3months old), aged (15months old) and lifelong exercise trained aged wild-type (WT) and whole-body PGC-1α knockout (KO) mice. Hepatic BiP, IRE1α and cleaved ATF6 protein content increased, whereas PERK protein content was reduced with aging indicating both increased and decreased capacity of specific UPR pathways and increased activity of the ATF6 pathway in the liver with aging. Lifelong exercise training prevented the age-associated change in BiP and IRE1α protein, but not cleaved ATF6 protein and resulted in further decreased PERK protein. Taken together, the present study provides evidence that the capacity and activity of the three UPR pathways are differentially regulated in the liver with aging and lifelong exercise training. In addition, PGC-1α does not seem to regulate the activity of hepatic UPR in response to exercise training, but to influence the capacity of the liver to induce UPR in a pathway specific manner.
衰老是与影响肝功能的几种代谢途径的变化相关联的，包括适应性未折叠蛋白反应 (UPR)。另一方面，运动训练已被证明对肝脏代谢具有有益影响，并且有报道称运动训练会影响肝 UPR。PGC-1α 是一种转录共激活因子，参与运动训练引起的骨骼肌和肝脏适应。因此，本研究的目的是研究 PGC-1α 在衰老和终生运动训练诱导的小鼠肝 UPR 中的作用。从小鼠（3 个月大）、老年（15 个月大）和终生运动训练的老年野生型 (WT) 和全身 PGC-1α 敲除 (KO) 小鼠中获得肝脏。肝 BiP、IRE1α 和切割 ATF6 蛋白含量增加，而 PERK 蛋白含量随着年龄的增长而减少，这表明特定 UPR 途径的能力增加和减少，以及 ATF6 途径的活性增加与衰老有关。终生运动训练可防止与年龄相关的 BiP 和 IRE1α 蛋白变化，但不能防止切割 ATF6 蛋白的变化，并导致 PERK 蛋白进一步减少。综上所述，本研究提供了证据表明，随着年龄的增长和终生运动训练，三种 UPR 途径的能力和活性在肝脏中受到不同的调节。此外，PGC-1α 似乎不会调节肝 UPR 对运动训练的活性，而是以特定途径的方式影响肝脏诱导 UPR 的能力。
