Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
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胰岛素受体底物对于心脏对运动训练的生物能和肥厚反应至关重要
DOI：
10.1128/mcb.00426-14
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发表时间：
2014
影响因子：
5.3
通讯作者：
Abel ED
中科院分区：
文献类型：
--
作者：
Riehle C;Wende AR;Oliveira KJ;Pereira RO;Jaishy BP;Bevins J;Valdez S;Kim BJ;Moreira AB;Weatherford ET;Manivel R;Rawlings TA;Rech M;White MF;Abel ED
胰岛素和胰岛素样生长因子1（IGF-1）受体信号通路在静息条件下和运动训练后差异调节心脏生长。这些作用是由胰岛素受体底物1（IRS 1）和IRS 2介导的，IRS 1和IRS 2也差异调节静息心脏质量。为了确定IRS亚型在介导心脏对运动训练的肥大和代谢适应中的作用，我们对IRS 1（CIRS 1敲除[CIRS 1 KO]小鼠）或IRS 2（CIRS 2KO小鼠）心肌细胞特异性缺失的小鼠进行游泳训练。在基础条件下，CIRS 1 KO心脏的尺寸减小，而CIRS 2KO心脏表现出肥大。在CIRS 1 KO和CIRS 2KO心脏中进行运动游泳训练后，肥大反应同等减弱，磷酸肌醇3-激酶（PI 3 K）激活减弱，促肥大信号传导中间体（如Akt和糖原合成酶激酶3β（GSK 3 β））可能在Janus激酶介导的蛋白磷酸酶2a（PP 2A）抑制降低的基础上去磷酸化。运动训练增加了野生型（WT）对照组的过氧化物酶体增殖物激活受体γ辅激活因子1-α（PGC-1α）蛋白含量、线粒体容量、脂肪酸氧化和糖原合成，但在IRS 1和IRS 2缺陷型心脏中没有。PGC-1α蛋白含量在CIRS 1 KO中保持不变，但在CIRS 2 KO心脏中下降。这些结果表明，虽然IRS异构体发挥不同的作用，在心脏大小的发育调节，这些异构体表现出非冗余的作用，在调解心脏的肥大和代谢反应的运动。
Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3β (GSK3β), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1- and IRS2-deficient hearts. PGC-1α protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
--
作者：
Kim, Jaetaek;Wende, Adam R.;Abel, E. Dale
通讯作者：
Abel, E. Dale
影响因子：
15.9
作者：
Mauvais-Jarvis, F;Ueki, K;Kahn, CR
通讯作者：
Kahn, CR
DOI：
--
发表时间：
2007
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
A. Wende;P. Schaeffer;G. Parker;C. Zechner;Dong‐Ho Han;May M. Chen;C. Hancock;J. J. Lehman-J.
通讯作者：
A. Wende;P. Schaeffer;G. Parker;C. Zechner;Dong‐Ho Han;May M. Chen;C. Hancock;J. J. Lehman-J.
DOI：
10.1152/ajpheart.00925.2003
发表时间：
2004-09-01
影响因子：
4.8
作者：
Burelle, Y;Wambolt, RB;Allard, MF
通讯作者：
Allard, MF