Giani Jorge F, Bonkowski Michael S, Muñoz Marina C, Masternak Michal M, Turyn Daniel, Bartke Andrzej, Dominici Fernando P
Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Buenos Aires, Buenos Aires 1113, Argentina.
J Gerontol A Biol Sci Med Sci. 2008 Aug;63(8):788-97. doi: 10.1093/gerona/63.8.788.
Calorie restriction (CR) improves insulin sensitivity and increases life span in normal but not in long-lived growth hormone-resistant knockout (GHRKO) mice. In this study, we examined interactive effects of GH resistance and long-term CR on cardiac insulin action. GHRKO mice exhibited marked increases in the insulin-induced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Akt, and ERK1/2 along with elevated insulin-stimulated IRS-1-associated regulatory subunit of phosphatidylinositol 3-kinase in the heart. These changes were associated with elevated protein levels of IR, IRS-1, and Akt and with a down-regulation of cardiac glucose transporter 4 (GLUT4). In normal mice, CR induced an important increase in the phosphorylation of cardiac Akt without elevation of Akt protein, reaching activation levels similar to those seen in GHRKO mice. This change may be cardioprotective and thus contribute to increased longevity in response to CR. Interestingly, the insulin signaling cascade in the heart of GHRKO mice was unaffected by CR.
热量限制（CR）可改善正常小鼠的胰岛素敏感性并延长其寿命，但对长寿的生长激素抵抗敲除（GHRKO）小鼠则无此作用。在本研究中，我们检测了生长激素抵抗和长期热量限制对心脏胰岛素作用的交互影响。GHRKO小鼠心脏中胰岛素诱导的胰岛素受体（IR）、胰岛素受体底物-1（IRS-1）、Akt和ERK1/2磷酸化显著增加，同时胰岛素刺激的IRS-1相关磷脂酰肌醇3激酶调节亚基升高。这些变化与IR、IRS-1和Akt蛋白水平升高以及心脏葡萄糖转运蛋白4（GLUT4）下调有关。在正常小鼠中，热量限制可使心脏Akt磷酸化显著增加，但Akt蛋白水平未升高，达到与GHRKO小鼠相似的激活水平。这种变化可能具有心脏保护作用，从而有助于热量限制延长寿命。有趣的是，GHRKO小鼠心脏中的胰岛素信号级联不受热量限制的影响。
