Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts.
Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts.
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DOI：
10.18632/aging.100881
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Rabinovitch PS
中科院分区：
文献类型：
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作者：
Chiao YA;Kolwicz SC;Basisty N;Gagnidze A;Zhang J;Gu H;Djukovic D;Beyer RP;Raftery D;MacCoss M;Tian R;Rabinovitch PS
雷帕霉素是一种mTOR信号传导抑制剂，已被证明可以在10周内逆转老年小鼠的舒张功能障碍，突出了其对可治疗性差的疾病的治疗潜力。然而，其心脏益处的机制和时间调节仍不清楚。我们发现，老年小鼠的舒张功能在2-4周开始改善，在10周的治疗过程中取得进展。虽然TORC 1介导的S6磷酸化和TORC 2介导的AKT和PKCα磷酸化在整个治疗过程中受到抑制，但雷帕霉素仅在治疗的第一周内抑制ULK磷酸化并诱导自噬，在两周及之后恢复至基线水平。一致地，线粒体生物发生的标志物在治疗的前两周内增加，此后恢复到对照水平。这种自噬和线粒体生物发生的短暂诱导表明，受损的线粒体被新合成的线粒体所取代，以恢复线粒体的稳态。这种重塑被证明可以快速逆转与年龄相关的脂肪酸氧化减少，以恢复更年轻的底物利用和充满活力的配置文件在旧的隔离灌注心脏，并在体内调节心肌代谢组。这项研究展示了雷帕霉素治疗后的差异和动态机制，并强调了理解雷帕霉素效应的时间调节的重要性。
Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment. While TORC1-mediated S6 phosphorylation and TORC2 mediated AKT and PKCα phosphorylation are inhibited throughout the course of treatment, rapamycin inhibits ULK phosphorylation and induces autophagy during just the first week of treatment, returning to baseline at two weeks and after. Concordantly, markers of mitochondrial biogenesis increase over the first two weeks of treatment and return to control levels thereafter. This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolome in vivo. This study demonstrates the differential and dynamic mechanisms following rapamycin treatment and highlights the importance of understanding the temporal regulation of rapamycin effects.