Hasumi Yukiko, Baba Masaya, Hasumi Hisashi, Huang Ying, Lang Martin, Reindorf Rachel, Oh Hyoung-bin, Sciarretta Sebastiano, Nagashima Kunio, Haines Diana C, Schneider Michael D, Adelstein Robert S, Schmidt Laura S, Sadoshima Junichi, Marston Linehan W
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA, IRCCS Neuromed, Località Camerelle, 86077, Pozzilli (IS), Italy.
Hum Mol Genet. 2014 Nov 1;23(21):5706-19. doi: 10.1093/hmg/ddu286. Epub 2014 Jun 6.
Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK-mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.
心脏肥大是一种对壁应力增加作出反应的适应性过程，其特征是心肌细胞增大和结构重塑。它受到各种生长信号的刺激，其中mTORC1途径是一个广为人知的来源。在此，我们表明，一种新型的AMPK-mTOR相互作用分子Fnlcn的缺失会导致严重的心脏肥大，能量稳态失调，进而导致小鼠扩张型心肌病。我们发现，在Fnlcn缺陷的心脏中mTORC1活性上调，而雷帕霉素治疗可显著减轻心脏重量并改善心脏功能障碍。在Fnlcn缺陷的心脏中，磷酸化的AMP激活蛋白激酶（AMPK）α（T172）减少，并且对包括二甲双胍和AICAR（5-氨基-1-β-D-呋喃核糖基-咪唑-4-甲酰胺）在内的各种刺激无反应。在Fnlcn缺陷的心脏中，ATP水平升高，线粒体功能增强，这表明在Fnlcn缺陷情况下线粒体代谢上调产生的过量能量可能会减弱AMPK的激活。线粒体代谢的核心分子Ppargc1a的表达在Fnlcn缺陷的心脏中增加，事实上，在Fnlcn缺陷的心脏中使Ppargc1a失活可显著减轻心脏重量并延长生存期。Ppargc1a失活可恢复Fnlcn缺陷心脏中的磷酸化AMPK-α水平并抑制mTORC1活性，这表明上调的Ppargc1a会导致线粒体代谢增加和能量过剩，从而导致AMPK失活和mTORC1激活。雷帕霉素治疗对Fnlcn/Ppargc1a双失活心脏的心脏大小没有影响，这进一步支持了Ppargc1a是导致AMPK-mTOR轴失调并在Fnlcn缺陷情况下导致心脏肥大的关键因素这一观点。这些数据支持了Fnlcn在小鼠模型心脏稳态中的重要作用。
