Zarzycka Weronika, Kobak Kamil A, King Catherine J, Peelor Frederick F, Miller Benjamin F, Chiao Ying Ann
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Geroscience. 2025 Apr;47(2):1823-1836. doi: 10.1007/s11357-024-01368-w. Epub 2024 Oct 9.
The mechanistic target of rapamycin complex 1 (mTORC1) has a major impact on aging by regulation of proteostasis. It is well established that mTORC1 signaling is hyperactivated with aging and age-related diseases. Previous studies have shown that partial inhibition of mTOR signaling by rapamycin reverses age-related deteriorations in cardiac function and structure in old mice. However, the downstream signaling pathways involved in this protection against cardiac aging have not been established. mTORC1 phosphorylates 4E-binding protein 1 (4EBP1) to promote the initiation of cap-dependent translation. The objective of this project is to examine the role of the mTORC1/4EBP1 axis in age-related cardiac dysfunction. We used a whole-body 4EBP1 KO mouse model, which mimics a hyperactive mTORC1/4EBP1/eIF4E axis, to investigate the effects of hyperactive mTORC1/4EBP1 axis in cardiac aging. Echocardiographic measurements of middle-aged 4EBP1 KO mice show impaired diastolic function and myocardial performance compared to age-matched WT mice and these parameters are at similar levels as old WT mice, suggesting that 4EBP1 KO mice experience accelerated cardiac aging. Old 4EBP1 KO mice show further decline in systolic and diastolic function compared to middle-aged counterparts and have worse systolic and diastolic function than age-matched WT mice. Gene expression levels of heart failure markers are not different between 4EBP1 KO and WT hearts. However, ribosomal biogenesis and protein ubiquitination are significantly increased in 4EBP1 KO hearts when compared to WT controls, suggesting dysregulated proteostasis in 4EBP1 KO hearts. Together, these results show that a hyperactive mTORC1/4EBP1 axis accelerates cardiac aging, potentially by dysregulating proteostasis.
雷帕霉素靶蛋白复合物1（mTORC1）通过调节蛋白质稳态对衰老产生重大影响。众所周知，mTORC1信号随着衰老和与年龄相关的疾病而过度激活。先前的研究表明，雷帕霉素对mTOR信号的部分抑制可逆转老年小鼠心脏功能和结构与年龄相关的衰退。然而，这种针对心脏衰老的保护作用所涉及的下游信号通路尚未明确。mTORC1使4E结合蛋白1（4EBP1）磷酸化，以促进帽依赖性翻译的起始。本项目的目的是研究mTORC1/4EBP1轴在与年龄相关的心脏功能障碍中的作用。我们使用了一种全身4EBP1基因敲除小鼠模型，该模型模拟了过度活跃的mTORC1/4EBP1/eIF4E轴，以研究过度活跃的mTORC1/4EBP1轴在心脏衰老中的作用。中年4EBP1基因敲除小鼠的超声心动图测量显示，与年龄匹配的野生型小鼠相比，其舒张功能和心肌性能受损，并且这些参数与老年野生型小鼠处于相似水平，这表明4EBP1基因敲除小鼠经历了加速的心脏衰老。与中年4EBP1基因敲除小鼠相比，老年4EBP1基因敲除小鼠的收缩和舒张功能进一步下降，并且其收缩和舒张功能比年龄匹配的野生型小鼠更差。4EBP1基因敲除小鼠和野生型小鼠心脏中的心衰标志物基因表达水平没有差异。然而，与野生型对照相比，4EBP1基因敲除小鼠心脏中的核糖体生物合成和蛋白质泛素化显著增加，这表明4EBP1基因敲除小鼠心脏中的蛋白质稳态失调。总之，这些结果表明，过度活跃的mTORC1/4EBP1轴可能通过失调蛋白质稳态来加速心脏衰老。
