Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309.
BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303.
Proc Natl Acad Sci U S A. 2024 Oct 8;121(41):e2408719121. doi: 10.1073/pnas.2408719121. Epub 2024 Oct 1.
As ambush-hunting predators that consume large prey after long intervals of fasting, Burmese pythons evolved with unique adaptations for modulating organ structure and function. Among these is cardiac hypertrophy that develops within three days following a meal (Andersen et al., 2005, Secor, 2008), which we previously showed was initiated by circulating growth factors (Riquelme et al., 2011). Postprandial cardiac hypertrophy in pythons also rapidly regresses with subsequent fasting (Secor, 2008); however, the molecular mechanisms that regulate the dynamic cardiac remodeling in pythons during digestion are largely unknown. In this study, we employed a multiomics approach coupled with targeted molecular analyses to examine remodeling of the python ventricular transcriptome and proteome throughout digestion. We found that forkhead box protein O1 (FoxO1) signaling was suppressed prior to hypertrophy development and then activated during regression, which coincided with decreased and then increased expression, respectively, of FoxO1 transcriptional targets involved in proteolysis. To define the molecular mechanistic role of FoxO1 in hypertrophy regression, we used cultured mammalian cardiomyocytes treated with postfed python plasma. Hypertrophy regression both in pythons and in vitro coincided with activation of FoxO1-dependent autophagy; however, the introduction of a FoxO1-specific inhibitor prevented both regression of cell size and autophagy activation. Finally, to determine whether FoxO1 activation could induce regression, we generated an adenovirus expressing a constitutively active FoxO1. FoxO1 activation was sufficient to prevent and reverse postfed plasma-induced hypertrophy, which was partially prevented by autophagy inhibition. Our results indicate that modulation of FoxO1 activity contributes to the dynamic ventricular remodeling in postprandial Burmese pythons.
作为埋伏型捕食者，缅甸蟒在长时间禁食后会捕食大型猎物，因此它们进化出了独特的适应机制来调节器官结构和功能。其中包括心肌肥大，这种现象在进食后三天内就会出现（Andersen 等人，2005 年；Secor，2008 年），我们之前的研究表明这是由循环生长因子引发的（Riquelme 等人，2011 年）。蟒蛇在进食后也会发生快速的心脏肥大消退（Secor，2008 年）；然而，调节蟒蛇在消化过程中心脏动态重塑的分子机制在很大程度上尚不清楚。在这项研究中，我们采用了一种多组学方法，并结合了靶向分子分析，以研究蟒蛇心室转录组和蛋白质组在消化过程中的重塑情况。我们发现，在心肌肥大发展之前，叉头框蛋白 O1（FoxO1）信号被抑制，然后在消退过程中被激活，这与涉及蛋白水解的 FoxO1 转录靶点的表达分别降低然后增加相对应。为了确定 FoxO1 在肥大消退中的分子机制作用，我们使用经进食后蟒蛇血浆处理的培养哺乳动物心肌细胞进行实验。蟒蛇和体外的肥大消退与 FoxO1 依赖性自噬的激活同时发生；然而，FoxO1 特异性抑制剂的引入阻止了细胞大小的消退和自噬的激活。最后，为了确定 FoxO1 激活是否可以诱导肥大消退，我们生成了一种表达组成型激活 FoxO1 的腺病毒。FoxO1 的激活足以防止和逆转由进食后血浆诱导的肥大，而自噬抑制部分阻止了肥大的发生。我们的研究结果表明，FoxO1 活性的调节有助于进食后缅甸蟒心室的动态重塑。
