J Clin Invest. 2013 Dec;123(12):5319-33. doi: 10.1172/JCI71171. Epub 2013 Nov 1.
The induction of autophagy in the mammalian heart during the perinatal period is an essential adaptation required to survive early neonatal starvation; however, the mechanisms that mediate autophagy suppression once feeding is established are not known. Insulin signaling in the heart is transduced via insulin and IGF-1 receptors (IGF-1Rs). We disrupted insulin and IGF-1R signaling by generating mice with combined cardiomyocyte-specific deletion of Irs1 and Irs2. Here we show that loss of IRS signaling prevented the physiological suppression of autophagy that normally parallels the postnatal increase in circulating insulin. This resulted in unrestrained autophagy in cardiomyocytes, which contributed to myocyte loss, heart failure, and premature death. This process was ameliorated either by activation of mTOR with aa supplementation or by genetic suppression of autophagic activation. Loss of IRS1 and IRS2 signaling also increased apoptosis and precipitated mitochondrial dysfunction, which were not reduced when autophagic flux was normalized. Together, these data indicate that in addition to prosurvival signaling, insulin action in early life mediates the physiological postnatal suppression of autophagy, thereby linking nutrient sensing to postnatal cardiac development.
在围产期,哺乳动物心脏中的自噬诱导是生存早期新生儿饥饿所必需的适应;然而,一旦开始喂养,介导自噬抑制的机制尚不清楚。心脏中的胰岛素信号通过胰岛素和 IGF-1 受体 (IGF-1R) 转导。我们通过生成具有心肌细胞特异性缺失 Irs1 和 Irs2 的小鼠来破坏胰岛素和 IGF-1R 信号。在这里,我们表明 IRS 信号的丧失阻止了自噬的生理抑制,而自噬通常与循环胰岛素的出生后增加平行。这导致心肌细胞中不受控制的自噬,导致心肌细胞损失、心力衰竭和过早死亡。通过 aa 补充激活 mTOR 或通过遗传抑制自噬激活可以改善这种情况。IRS1 和 IRS2 信号的丧失也增加了细胞凋亡并加剧了线粒体功能障碍,而当自噬通量正常化时,这些并没有减少。总之,这些数据表明,除了生存信号外,胰岛素在生命早期的作用还介导了自噬的生理性出生后抑制,从而将营养感应与出生后心脏发育联系起来。