Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy
Insulin-Like Growth Factor I Receptor Signaling Is Required for Exercise-Induced Cardiac Hypertrophy
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DOI：
10.1210/me.2008-0265
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发表时间：
2008-11-01
影响因子：
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通讯作者：
Abel, E. Dale
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文献类型：
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作者：
Kim, Jaetaek;Wende, Adam R.;Abel, E. Dale
胰岛素样生长因子-I受体(IGF-IR)和胰岛素(IR)参与了心脏生理性生长，但目前尚不清楚IGF-IR或IR信号是否是心脏生理性生长所必需的。我们建立了心肌细胞特异性IGF-IR基因敲除的小鼠(CIGF1RKO)，并将它们与心肌细胞特异性胰岛素受体基因敲除(Cirko)小鼠在5wk运动游泳训练中进行了比较。CIGF1RKO小鼠心脏发育正常，但运动引起的肥大反应被阻止。相比之下，尽管基线心脏大小减小，Cirko心脏对运动的肥大反应被保留下来。运动增加对照组和Cirko心脏中IGF-IR的含量。在运动训练的对照组和Cirko心脏中，AKT的磷酸化增加，令人惊讶的是，在CIGF1RKO心脏中也是如此。在运动对照组和Cirko小鼠中，PGC-1α的表达和糖原含量在训练后的CIGF1RKO小鼠中均增加，但没有变化。AMP激活的蛋白激酶(AMPK)及其下游靶真核延长因子-2的活性在运动训练的CIGF1RKO中增加，但在Cirko或对照心脏中不增加。在培养的乳鼠心肌细胞上，用5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核苷(AICAR)激活AMPK可阻止IGF-I/胰岛素诱导的心肌细胞肥大。这些研究确定了IGF-IR在调节生理性心肌细胞肥大中的重要作用。IGF-IR缺乏促进运动所致的能量应激，从而激活AMPK，从而导致真核细胞延伸因子-2的磷酸化。这些信号事件拮抗Akt信号，虽然Akt信号是调节生理性心肌肥大所必需的，但在缺乏心肌IGF-I信号的情况下，不足以促进心肌肥厚。(分子内分泌学22：2531-2543,2008)
The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of IGF-IR (CIGF1RKO) and compared them with cardiomyocyte-specific insulin receptor knockout (CIRKO) mice in response to 5 wk exercise swim training. Cardiac development was normal in CIGF1RKO mice, but the hypertrophic response to exercise was prevented. In contrast, despite reduced baseline heart size, the hypertrophic response of CIRKO hearts to exercise was preserved. Exercise increased IGF-IR content in control and CIRKO hearts. Akt phosphorylation increased in exercise-trained control and CIRKO hearts and, surprisingly, in CIGF1RKO hearts as well. In exercise-trained control and CIRKO mice, expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) and glycogen content were both increased but were unchanged in trained CIGF1RKO mice. Activation of AMP-activated protein kinase (AMPK) and its downstream target eukaryotic elongation factor-2 was increased in exercise-trained CIGF1RKO but not in CIRKO or control hearts. In cultured neonatal rat cardiomyocytes, activation of AMPK with 5-amino-imidazole-4- carboxamide-1-beta-D-ribofuranoside (AICAR) prevented IGF-I/insulin-induced cardiomyocyte hypertrophy. These studies identify an essential role for IGF- IR in mediating physiological cardiomyocyte hypertrophy. IGF- IR deficiency promotes energetic stress in response to exercise, thereby activating AMPK, which leads to phosphorylation of eukaryotic elongation factor-2. These signaling events antagonize Akt signaling, which although necessary for mediating physiological cardiac hypertrophy, is insufficient to promote cardiac hypertrophy in the absence of myocardial IGF-I signaling. (Molecular Endocrinology 22: 2531-2543, 2008)